Polyphenols as Immunomodulatory Compounds in the Tumor Microenvironment: Friends or Foes?
Identifieur interne : 000482 ( Pmc/Checkpoint ); précédent : 000481; suivant : 000483Polyphenols as Immunomodulatory Compounds in the Tumor Microenvironment: Friends or Foes?
Auteurs : Chiara Focaccetti ; Valerio Izzi ; Monica Benvenuto ; Sara Fazi ; Sara Ciuffa ; Maria Gabriella Giganti ; Vito Potenza ; Vittorio Manzari ; Andrea Modesti ; Roberto BeiSource :
- International Journal of Molecular Sciences [ 1422-0067 ] ; 2019.
Abstract
Polyphenols are natural antioxidant compounds ubiquitously found in plants and, thus, ever present in human nutrition (tea, wine, chocolate, fruits and vegetables are typical examples of polyphenol-rich foods). Widespread evidence indicate that polyphenols exert strong antioxidant, anti-inflammatory, anti-microbial and anti-cancer activities, and thus, they are generally regarded to as all-purpose beneficial nutraceuticals or supplements whose use can only have a positive influence on the body. A closer look to the large body of results of years of investigations, however, present a more complex scenario where polyphenols exert different and, sometimes, paradoxical effects depending on dose, target system and cell type and the biological status of the target cell. Particularly, the immunomodulatory potential of polyphenols presents two opposite faces to researchers trying to evaluate their usability in future cancer therapies: on one hand, these compounds could be beneficial suppressors of peri-tumoral inflammation that fuels cancer growth. On the other hand, they might suppress immunotherapeutic approaches and give rise to immunosuppressive cell clones that, in turn, would aid tumor growth and dissemination. In this review, we summarize knowledge of the immunomodulatory effects of polyphenols with a particular focus on cancer microenvironment and immunotherapy, highlighting conceptual pitfalls and delicate cell-specific effects in order to aid the design of future therapies involving polyphenols as chemoadjuvants.
Url:
DOI: 10.3390/ijms20071714
PubMed: 30959898
PubMed Central: 6479528
Affiliations:
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<front><div type="abstract" xml:lang="en"><p>Polyphenols are natural antioxidant compounds ubiquitously found in plants and, thus, ever present in human nutrition (tea, wine, chocolate, fruits and vegetables are typical examples of polyphenol-rich foods). Widespread evidence indicate that polyphenols exert strong antioxidant, anti-inflammatory, anti-microbial and anti-cancer activities, and thus, they are generally regarded to as all-purpose beneficial nutraceuticals or supplements whose use can only have a positive influence on the body. A closer look to the large body of results of years of investigations, however, present a more complex scenario where polyphenols exert different and, sometimes, paradoxical effects depending on dose, target system and cell type and the biological status of the target cell. Particularly, the immunomodulatory potential of polyphenols presents two opposite faces to researchers trying to evaluate their usability in future cancer therapies: on one hand, these compounds could be beneficial suppressors of peri-tumoral inflammation that fuels cancer growth. On the other hand, they might suppress immunotherapeutic approaches and give rise to immunosuppressive cell clones that, in turn, would aid tumor growth and dissemination. In this review, we summarize knowledge of the immunomodulatory effects of polyphenols with a particular focus on cancer microenvironment and immunotherapy, highlighting conceptual pitfalls and delicate cell-specific effects in order to aid the design of future therapies involving polyphenols as chemoadjuvants.</p>
</div>
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<author><name sortKey="Lou, H" uniqKey="Lou H">H. Lou</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Sci</journal-id>
<journal-id journal-id-type="iso-abbrev">Int J Mol Sci</journal-id>
<journal-id journal-id-type="publisher-id">ijms</journal-id>
<journal-title-group><journal-title>International Journal of Molecular Sciences</journal-title>
</journal-title-group>
<issn pub-type="epub">1422-0067</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">30959898</article-id>
<article-id pub-id-type="pmc">6479528</article-id>
<article-id pub-id-type="doi">10.3390/ijms20071714</article-id>
<article-id pub-id-type="publisher-id">ijms-20-01714</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Review</subject>
</subj-group>
</article-categories>
<title-group><article-title>Polyphenols as Immunomodulatory Compounds in the Tumor Microenvironment: Friends or Foes?</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7334-3966</contrib-id>
<name><surname>Focaccetti</surname>
<given-names>Chiara</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-01714">1</xref>
<xref ref-type="author-notes" rid="fn1-ijms-20-01714">†</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-9960-4917</contrib-id>
<name><surname>Izzi</surname>
<given-names>Valerio</given-names>
</name>
<xref ref-type="aff" rid="af2-ijms-20-01714">2</xref>
<xref ref-type="author-notes" rid="fn1-ijms-20-01714">†</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2520-1306</contrib-id>
<name><surname>Benvenuto</surname>
<given-names>Monica</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-01714">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fazi</surname>
<given-names>Sara</given-names>
</name>
<xref ref-type="aff" rid="af3-ijms-20-01714">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ciuffa</surname>
<given-names>Sara</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-01714">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Giganti</surname>
<given-names>Maria Gabriella</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-01714">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Potenza</surname>
<given-names>Vito</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-01714">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Manzari</surname>
<given-names>Vittorio</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-01714">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Modesti</surname>
<given-names>Andrea</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-01714">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-9541-8896</contrib-id>
<name><surname>Bei</surname>
<given-names>Roberto</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-20-01714">1</xref>
<xref rid="c1-ijms-20-01714" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-ijms-20-01714"><label>1</label>
Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;<email>chiara_focaccetti@hotmail.com</email>
(C.F.);<email>monicab4@hotmail.it</email>
(M.B.);<email>saramhh@hotmail.it</email>
(S.C.);<email>giganti@med.uniroma2.it</email>
(M.G.G.);<email>vitopotenza2@virgilio.it</email>
(V.P.);<email>manzari@med.uniroma2.it</email>
(V.M.);<email>modesti@med.uniroma2.it</email>
(A.M.)</aff>
<aff id="af2-ijms-20-01714"><label>2</label>
Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland;<email>valerio.izzi@oulu.fi</email>
</aff>
<aff id="af3-ijms-20-01714"><label>3</label>
Department of Experimental Medicine, University of Rome “Sapienza”, 00164 Rome, Italy;<email>sarafazi@hotmail.it</email>
</aff>
<author-notes><corresp id="c1-ijms-20-01714"><label>*</label>
Correspondence: <email>bei@med.uniroma2.it</email>
</corresp>
<fn id="fn1-ijms-20-01714"><label>†</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>06</day>
<month>4</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>4</month>
<year>2019</year>
</pub-date>
<volume>20</volume>
<issue>7</issue>
<elocation-id>1714</elocation-id>
<history><date date-type="received"><day>28</day>
<month>2</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>03</day>
<month>4</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract><p>Polyphenols are natural antioxidant compounds ubiquitously found in plants and, thus, ever present in human nutrition (tea, wine, chocolate, fruits and vegetables are typical examples of polyphenol-rich foods). Widespread evidence indicate that polyphenols exert strong antioxidant, anti-inflammatory, anti-microbial and anti-cancer activities, and thus, they are generally regarded to as all-purpose beneficial nutraceuticals or supplements whose use can only have a positive influence on the body. A closer look to the large body of results of years of investigations, however, present a more complex scenario where polyphenols exert different and, sometimes, paradoxical effects depending on dose, target system and cell type and the biological status of the target cell. Particularly, the immunomodulatory potential of polyphenols presents two opposite faces to researchers trying to evaluate their usability in future cancer therapies: on one hand, these compounds could be beneficial suppressors of peri-tumoral inflammation that fuels cancer growth. On the other hand, they might suppress immunotherapeutic approaches and give rise to immunosuppressive cell clones that, in turn, would aid tumor growth and dissemination. In this review, we summarize knowledge of the immunomodulatory effects of polyphenols with a particular focus on cancer microenvironment and immunotherapy, highlighting conceptual pitfalls and delicate cell-specific effects in order to aid the design of future therapies involving polyphenols as chemoadjuvants.</p>
</abstract>
<kwd-group><kwd>polyphenols</kwd>
<kwd>cancer</kwd>
<kwd>immune response</kwd>
<kwd>inflammation</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="ijms-20-01714-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Chemical structures of polyphenols. Dietary polyphenols can be classified by their chemical structures into flavonoids and non-flavonoids. Structures generated using ChemDraw JS 17.1 (CambridgeSoft Corp., Cambridge, MA, USA).</p>
</caption>
<graphic xlink:href="ijms-20-01714-g001"></graphic>
</fig>
<fig id="ijms-20-01714-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Effects of polyphenols on immune cells. The more common activities of polyphenols on immune cells and cytokines are reported.</p>
</caption>
<graphic xlink:href="ijms-20-01714-g002"></graphic>
</fig>
<table-wrap id="ijms-20-01714-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">ijms-20-01714-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>In vitro and in vivo effect of polyphenols on immune cells.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"></th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cell Type</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Treatment</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">In Vitro Model</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">In Vivo Model</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Effect on Immune System</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th>
</tr>
</thead>
<tbody><tr><td rowspan="7" align="center" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" colspan="1">MOUSE</td>
<td rowspan="7" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">SPLENOCYTES</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CHR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Wistar rat, LPS o lectin-stimulated, 3–25 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ proliferation (LPS)<break></break>
↑ proliferation (lectin)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B78-ijms-20-01714" ref-type="bibr">78</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c, + ConA 1 µg/mL or LPS 5 µg/mL + CUR 1–20 µM, 72 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ T cell proliferation (ConA)<break></break>
↓ IL-4, IFN-γ secretion<break></break>
↓ B cell proliferation (LPS)<break></break>
↓ IgG1, IgG2 production<break></break>
↔ viability</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-ijms-20-01714" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HSP</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Wistar rat, LPS or lectin-stimulated splenocytes, 3–25 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ proliferation (LPS)<break></break>
↓ proliferation (lectin)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B78-ijms-20-01714" ref-type="bibr">78</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">JSE</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ C57BL/6, 1–200 µg/mL, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ proliferation</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B85-ijms-20-01714" ref-type="bibr">85</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c, + ConA 1 µg/mL or LPS 5 µg/mL + RES 1–20 µM, 72 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ T cell proliferation (ConA)<break></break>
↓ IL-4, IFN-γ secretion<break></break>
↓ B cell proliferation (LPS)<break></break>
↓ IgG1, IgG2 production<break></break>
↔ viability</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-ijms-20-01714" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IL2 + ConA stimulation</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ A/J bearing neuroblastoma (NXS2) s.c., 20 mg p.t./every 3 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↔ circulating leukocyte population<break></break>
↑ tumor infiltrating leukocytes (CD45<sup>+</sup>
)<break></break>
↓ splenocytes proliferation<break></break>
↓ ADCC</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B76-ijms-20-01714" ref-type="bibr">76</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ C3H (H-2k) splenocytes, IL-2 or ConA-stimulated + RES 6, 25–50 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ C3H (H-2k) RES p.o. 2 mg/day, 5 days/week, 4 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ proliferation (RES 6.25–12.5 µM)<break></break>
↓ proliferation (RES 25–50 µM)<break></break>
↔ body weight<break></break>
↔ peripheral blood cell count<break></break>
↔ IFN-γ secretion (ConA-stimulated splenocytes)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B79-ijms-20-01714" ref-type="bibr">79</xref>
]</td>
</tr>
<tr><td rowspan="9" align="center" valign="middle" style="border-bottom:solid thin;background:#A6A6A6" colspan="1">HUMAN</td>
<td rowspan="9" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">PERIPHERAL BLOOD MONONUCLEAR CELLS</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC healthy donor, 0–60 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-6, IL-10; <break></break>
↑ TNF-α; <break></break>
↔ IFN-γ, IL-1ra, IL-1b</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B109-ijms-20-01714" ref-type="bibr">109</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HT</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC healthy donor, pre-treated HT 0.25–1 µM, 30′ + treated Oxysterols mixture 20 µM, 24 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-1b, MIF, RANTES<break></break>
↓ intracellular ROS production<break></break>
↓ p-JNK1/2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B75-ijms-20-01714" ref-type="bibr">75</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TYR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC healthy donor, pre-treated TYR 0.25–1 µM, 30′ + treated Oxysterols mixture 20 µM, 24 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-1b, MIF, RANTES<break></break>
↓ intracellular ROS production<break></break>
↓p-JNK1/2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B75-ijms-20-01714" ref-type="bibr">75</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HVA</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC healthy donor, pre-treated HVA 0.25–1 µM, 30′ + treated Oxysterols mixture 20 µM, 24 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-1b, MIF, RANTES<break></break>
↓ intracellular ROS production<break></break>
↓p-JNK1/2 (1 µM)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B75-ijms-20-01714" ref-type="bibr">75</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC healthy donor, PHA stimulated, 1–50 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ PBMC proliferation<break></break>
↓ ADCC</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B76-ijms-20-01714" ref-type="bibr">76</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC healthy donors, HT29, 0–60 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-6, IL-10, TNF-α, IFN-γ, IL-1ra, IL-1b</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B109-ijms-20-01714" ref-type="bibr">109</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC healthy donors, RKO, 0–60 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-1b, IFN-γ, IL-10<break></break>
↔ IL-6 and IL-1ra<break></break>
↑ TNF-α</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B109-ijms-20-01714" ref-type="bibr">109</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Linalool</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lymphocytes healthy donor, 227 µM, 24 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD40-ligand, CD40, IFN-γ, IL-12 p40, IL-13, IL-17F, IL-1β, IL-2, IL-21, IL-21R, IL-23p19, IL-4, IL-6Sr, TNF-α</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B77-ijms-20-01714" ref-type="bibr">77</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGCG</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast cancer patients, PBMC stimulated with PHA, anti-CD3, or Her2/neu and p53 antigen peptides, EGCG 0.125–50 µg/mL</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ PBMC proliferation > 10 µg/mL<break></break>
↓ IFN-γ production > 10 µg/mL</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B80-ijms-20-01714" ref-type="bibr">80</xref>
]</td>
</tr>
<tr><td rowspan="14" align="center" valign="middle" style="border-bottom:solid thin;background:#D9D9D9" colspan="1">MOUSE</td>
<td rowspan="14" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">MACROPHAGES</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CA</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Swiss albino bearing Ehrlich ascites tumor (EAT) cells</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ macrophages count<break></break>
↑ macrophages cytotoxicity<break></break>
↓ ARG1; ↔ NO<break></break>
↔ neutrophils, lymphocytes count</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B84-ijms-20-01714" ref-type="bibr">84</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CHR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Wistar rat, LPS o lectin-stimulated splenocytes, 3–25 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ macrophage lysosomal enzyme activity<break></break>
↓ NO production</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B78-ijms-20-01714" ref-type="bibr">78</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c, peritoneal macrophages, LPS stimulated + 1–20 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-1, IL-6, TNF-α<break></break>
↑ IL-10<break></break>
↓ CD80, CD86 expression<break></break>
↔ CD40 expression</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-ijms-20-01714" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">EGCG</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Balb/c bearing leukemia cells (WEHI-3), 5–40 mg/kg p.o.</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ phagocytosis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B81-ijms-20-01714" ref-type="bibr">81</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Balb/c bearing mammary cancer cells (4T1) s.c., EGCG i.p. 10 mg/kg, day 7-day 9-day 11</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ infiltration TAM and M2<break></break>
↓ CSF-1, CCL-2<break></break>
↓ IL-6, TGF-β<break></break>
↑ TNF-α</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B82-ijms-20-01714" ref-type="bibr">82</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HSP</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Wistar rat, LPS o lectin-stimulated splenocytes, HSP 3–25 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ macrophage lysosomal enzyme activity<break></break>
↔ NO production</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B78-ijms-20-01714" ref-type="bibr">78</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">P2Et</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma cells (B16F10), 72.7 µg/mL, 36 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">C57BL/6 bearing melanoma cells (B16F10) s.c., 75 mg/mL</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD45<sup>+</sup>
CD220<sup>−</sup>
CD11c<sup>+</sup>
<break></break>
↑ CD86, CD40, MHCII, CD70<break></break>
↑ BMDCs phagocytosis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B92-ijms-20-01714" ref-type="bibr">92</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 Healthy, 75 mg/kg i.p., twice/week/3weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ DCs,<break></break>
↑ MDSC-LC</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c Healthy, 75 mg/kg i.p., twice/week/5 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ DCs<break></break>
↑ MDSC-LC</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ C57BL/6, EG7 cells, BMDC pre-treated 1 h, 20–50 µM + 18 h IFN-γ 100 U/mL</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IDO expression<break></break>
↓ IRF-1 expression<break></break>
↓ STAT1, PKCδ</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B89-ijms-20-01714" ref-type="bibr">89</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c, peritoneal macrophages, LPS stimulated + 1–20 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-1, IL-6, TNF-α<break></break>
↑ IL-10<break></break>
↓ CD80, CD86 expression<break></break>
↔ CD40 expression</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-ijms-20-01714" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rutin</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Balb/c bearing leukemia cells (WEHI-3), macrophages from PBMC or peritoneum, 6–12 mg/kg, p.o., 3 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ phagocytosis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B83-ijms-20-01714" ref-type="bibr">83</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TrLp</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ C57BL/6 bearing Glioblastoma cells (GL261) i.c. implanted, TrLp 1,28 mM, i.p., every 24 h, 5 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Switch from M2-like TAM ARG1<sup>high</sup>
iNOS<sup>low</sup>
to M1-like TAM phenotype ARG1<sup>low</sup>
iNOS<sup>high</sup>
<break></break>
↑ NO production</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B87-ijms-20-01714" ref-type="bibr">87</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">C57BL/6 bearing Lung cancer cell (HPV<sup>+</sup>
TC-1), 64 µM, i.t. infusion every 24 h, 5 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">‘tumor-core’: E6<sup>+</sup>
tumor cells, ‘tumor-periphery’: Iba1<sup>+</sup>
TAM<break></break>
Switch from ARG1<sup>high</sup>
iNOS<sup>low</sup>
IL-12<sup>low</sup>
IL-10<sup>high</sup>
M2 TAM to ARG1<sup>low</sup>
iNOS<sup>high</sup>
IL-12<sup>high</sup>
IL-10<sup>low</sup>
M1 TAM<break></break>
↑ NO<break></break>
↓ p-STAT3<break></break>
↑ p-STAT1, p-NF-Kb</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B86-ijms-20-01714" ref-type="bibr">86</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin;background:#A6A6A6" colspan="1">HUMAN</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">MACROPHAGES</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">JSE</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">JSE, 1–200 µg/mL, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ phagocytosis, <break></break>
↑ NO, <break></break>
↑ H<sub>2</sub>
O<sub>2</sub>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B85-ijms-20-01714" ref-type="bibr">85</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TrLp</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HNSCC cells (UMSCC47);<break></break>
Nu/nu mice<break></break>
i.t. TrLp thrice/week/5weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Switch from ARG1<sup>high</sup>
iNOS<sup>low</sup>
<break></break>
Iba1<sup>+</sup>
M2 Macrophages to Iba1<sup>+</sup>
TAM ARG1<sup>low</sup>
iNOS<sup>high</sup>
M1<break></break>
↓ p-STAT3<break></break>
↑ p-STAT1, p-NF-kB<break></break>
↑ NO</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B86-ijms-20-01714" ref-type="bibr">86</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nano-CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–50 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↔ CD80, CCR7<break></break>
↑ CD86<break></break>
↔ TNF-α, IL-6, IL-12</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B94-ijms-20-01714" ref-type="bibr">94</xref>
]</td>
</tr>
<tr><td rowspan="19" align="center" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" colspan="1">MOUSE</td>
<td rowspan="19" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">T LYMPHOCYTES</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CHR or HSP</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Wistar rat, LPS o lectin-stimulated splenocytes, CHR or HSP 3–25 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CTL activity against B16F10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B78-ijms-20-01714" ref-type="bibr">78</xref>
]</td>
</tr>
<tr><td rowspan="6" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c splenocytes, + ConA 1 µg/mL + CUR 1–20 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD28 expression on CD4<break></break>
↑ CTLA-4 expression on CD4<break></break>
↓ proliferation T cells<break></break>
↓ IFN-γ, IL-4 secretion</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-ijms-20-01714" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing mammary cancer cells (TUBO) s.c., CUR p.o. 2 mg/50 µL oil, 3 days/week, ± CQ 2 mg/50 µL water, 5 days/week</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8, <break></break>
↓ Foxp3 Treg cells<break></break>
↓ CD8, ↑Foxp3 Treg cells, (CUR+CQ)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B97-ijms-20-01714" ref-type="bibr">97</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing oral carcinoma 4NQO-induced in drinking water for 16 weeks, CUR 4 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8 in tumor microenvironment</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B100-ijms-20-01714" ref-type="bibr">100</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing Lewis lung carcinoma (LLC), splenic lymphocytes isolation, activation and treatment with CUR 1.5 µg/mL, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ frequency and number of T cells (CUR < 1.5 µg/mL)<break></break>
↔ frequency and number of B cells, DCs, NK<break></break>
↓ frequency and number of T cells (CUR > 2 µg/mL)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B101-ijms-20-01714" ref-type="bibr">101</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing Lewis lung carcinoma cells (LLC), CUR 0–100 mg/kg/day/mouse, 10 days, i.p.</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8 cytotoxicity and proliferation (CUR < 1.5 µg/mL)<break></break>
↑IFN-γ</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B101-ijms-20-01714" ref-type="bibr">101</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ C57BL/6 BMDC LPS-matured, treated CUR 0–25 µM, 45′</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ BMDCs maturation<break></break>
↓ CD80, CD86, MHCII<break></break>
↓ IL-1, IL-6, TNF-α<break></break>
↓ T cell activation<break></break>
↓ IFN-γ production</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B102-ijms-20-01714" ref-type="bibr">102</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGCG</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Balb/c bearing leukemia (WEHI-3) cells, 5–40 mg/kg p.o.</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD3<sup>+</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B81-ijms-20-01714" ref-type="bibr">81</xref>
]</td>
</tr>
<tr><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">P2Et</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Vaccination with melanoma cells (B16F10) pre-treated with 101.6 µg/mL P2Et, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8<sup>+</sup>
CD44<sup>+</sup>
, CD8<sup>+</sup>
CD44<sup>+</sup>
CD62L<sup>+</sup>
<break></break>
↑ CD8<sup>+</sup>
IFN-γ<sup>+</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B92-ijms-20-01714" ref-type="bibr">92</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing melanoma cells (B16F10), 75 mg/kg, i.p. twice/week/10 days + s.c. twice/week/21 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD3<sup>+</sup>
, CD4<sup>+</sup>
, CD8<sup>+</sup>
(LN)<break></break>
↓ CD44<sup>+</sup>
(LN)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 Healthy, 75 mg/kg i.p., twice/week/3 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD4<sup>+</sup>
, CD8<sup>+</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing mouse mammary cancer cells (4T1) cells, 75 mg/kg, i.p. twice/week/10 days + s.c. twice/week/32 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD3<sup>+</sup>
, CD4<sup>+</sup>
, CD8<sup>+</sup>
(LN)<break></break>
↔ CD44<sup>+</sup>
(LN)<break></break>
↓ CD4<sup>+</sup>
T<sub>EM</sub>
↑ CD8<sup>+</sup>
T<sub>N</sub>
↓ CD8<sup>+</sup>
T<sub>EM</sub>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c Healthy,75 mg/kg i.p., twice/week/5 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD4<sup>+</sup>
, CD8<sup>+</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing renal adenocarcinoma cells (RENCA), 1–5 mg/kg, i.p.</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8 density; ↑CD69<sup>+</sup>
<break></break>
↑ CD8 Perforin, Granzyme B, FasL</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B93-ijms-20-01714" ref-type="bibr">93</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 spleen of T cell lymphoma (EG7)-bearing mice, 25–75 µM RES, 24 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6, i.p. 4 mg/kg RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8<sup>+</sup>
IFN-γ<sup>+</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B103-ijms-20-01714" ref-type="bibr">103</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ C57BL/6 OT-1; CD8 co-cultured with DC pulsed with OVA + 18 h IFN-γ 100 U/mL</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8 proliferation<break></break>
↑ CTL activity</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B89-ijms-20-01714" ref-type="bibr">89</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c splenocytes, ConA, RES 1–20 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD28 expression on CD4<sup>+</sup>
<break></break>
↔ CTLA-4 expression on CD4<sup>+</sup>
<break></break>
↓ proliferation T cells<break></break>
↓ IFN-γ, IL-4 secretion</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-ijms-20-01714" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rutin</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Balb/c bearing leukemia cells (WEHI-3), macrophages from PBMC or peritoneum, 6–12 mg/kg, p.o., 3 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD3, CD19<break></break>
↓ CD11b, Mac3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B83-ijms-20-01714" ref-type="bibr">83</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TrLp</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">C57BL/6 bearing Lung cancer cell (HPV<sup>+</sup>
TC-1), TrLp 64µM, i.t. infusion/every 24 h/5 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8<sup>+</sup>
CTL</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B86-ijms-20-01714" ref-type="bibr">86</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin;background:#A6A6A6" colspan="1">HUMAN</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">T LYMPHOCYTES</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Nano-CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–50 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↔ phenotype resting T cells<break></break>
↔ cytokine production in resting T cells<break></break>
↓ TNF-α, IL-6, IL-8, IL-10, IL-1b in activated T cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B94-ijms-20-01714" ref-type="bibr">94</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral carcinoma (OE19), 50 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CTLs lysis<break></break>
↔ TNF-α, IL-8, IFN-γ, IL-2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B94-ijms-20-01714" ref-type="bibr">94</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral carcinoma (OE33), 50 µM, 48 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CTLs lysis<break></break>
↑ IFN-γ<break></break>
↓ IL-8<break></break>
↔ TNF-α, IL-2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B94-ijms-20-01714" ref-type="bibr">94</xref>
]</td>
</tr>
<tr><td rowspan="13" align="center" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" colspan="1">MOUSE</td>
<td rowspan="13" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">T REGULATORY CELLS AND MIELOID DERIVED SUPPRESOR CELLS</td>
<td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c splenocytes, + ConA 1 µg/mL + CUR 1–20 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↔ frequency CD4<sup>+</sup>
CD25<sup>+</sup>
Treg cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-ijms-20-01714" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing oral carcinoma 4NQO-induced in drinking water for 16 weeks, CUR 4 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Treg cells (CD4<sup>+</sup>
CD25<sup>+</sup>
Foxp3<sup>+</sup>
)<break></break>
↓ MDSCs (CD11b<sup>+</sup>
GR1<sup>+</sup>
)<break></break>
↑ CD8<sup>+</sup>
in tumor microenvironment<break></break>
↓ PD-L1, p-STAT3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B100-ijms-20-01714" ref-type="bibr">100</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing melanoma cells (B16F10) s.c., treated with CUR-PEG and LCP Trp2-based vaccine</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ MDSCs<break></break>
↓ Treg cells<break></break>
↑ CD8+</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B95-ijms-20-01714" ref-type="bibr">95</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing Lewis lung carcinoma cells (LLC), 50 mg/kg p.o. daily</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ MDSCs<break></break>
↓ ARG1, iNOS, ROS<break></break>
↑ F4/80, MHCII, CD80, CD11c<break></break>
↑ CD8<sup>+</sup>
, CD4<sup>+</sup>
<break></break>
↓ IL-6 in tumor microenvironment</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B105-ijms-20-01714" ref-type="bibr">105</xref>
]</td>
</tr>
<tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">P2Et </td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing melanoma cells (B16F10) cells, 75 mg/kg, i.p. twice/week/10 days + s.c. twice/week/21 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ MDSC-LC cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" rowspan="1" colspan="1">♀ C57BL/6 Healthy, 75 mg/kg i.p., twice/week/3 weeks</td>
<td align="left" valign="middle" rowspan="1" colspan="1">↑ CTLA-4<sup>+</sup>
, Foxp3<sup>+</sup>
Treg cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing mammary cancer cells (4T1) cells, 75 mg/kg, i.p. twice/week/10 days + s.c. twice/week/32 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ MDSC-LC cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c Healthy,75 mg/kg i.p., twice/week/5 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CTLA-4<sup>+</sup>
, Foxp3<sup>+</sup>
Treg cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing renal carcinoma cells (RENCA) cells, i.p. 1–5 mg/kg</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↔ frequency</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B93-ijms-20-01714" ref-type="bibr">93</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing renal carcinoma cells (RENCA) cells, i.p. 1–5 mg/kg</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ frequency</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B93-ijms-20-01714" ref-type="bibr">93</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c splenocytes, + ConA 1 µg/mL + RES 1–20 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↔ frequency CD4<sup>+</sup>
CD25<sup>+</sup>
Treg cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-ijms-20-01714" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 spleen of T cell lymphoma (EG7)-bearing mice, 25–75 µM RES, 24 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing T cell lymphoma (EG7), i.p. 4 mg/kg</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD4<sup>+</sup>
CD25<sup>+</sup>
FoxP3<sup>+</sup>
<break></break>
↓ CD4<sup>+</sup>
CD25<sup>+</sup>
/CD4<sup>+</sup>
ratio<break></break>
↓ TGF-b<break></break>
↑ CD8+IFN-γ<sup>+</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B103-ijms-20-01714" ref-type="bibr">103</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c spleen of colon cancer (CT-26)-bearing mice, 25–75 µM, 24 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD4<sup>+</sup>
CD25<sup>+</sup>
FoxP3<sup>+</sup>
<break></break>
↓ CD4<sup>+</sup>
CD25<sup>+</sup>
/CD4<sup>+</sup>
ratio</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B103-ijms-20-01714" ref-type="bibr">103</xref>
]</td>
</tr>
<tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin;background:#A6A6A6" colspan="1">HUMAN</td>
<td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">T REGULATORY CELLS</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC from Lung cancer patients treated 3 g/day, 2 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">convert (CD4<sup>+</sup>
CD25<sup>+</sup>
Foxp3<sup>+</sup>
) Treg cells into IFN-γ<sup>+</sup>
Th1 cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B106-ijms-20-01714" ref-type="bibr">106</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBMC from advanced colon carcinoma patients treated 3 g/day, 2 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Treg cells (CD4<sup>+</sup>
CD25<sup>+</sup>
Foxp3<sup>+</sup>
)<break></break>
↑ CD4<sup>+</sup>
CD25<sup>+</sup>
Foxp3<sup>−</sup>
, IFN-γ<sup>+</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B106-ijms-20-01714" ref-type="bibr">106</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGCG, GTE</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CLL patients (Rai stage 0), 6 months, 4602 mg of green tea leaves, 189 mg EGCG, 97,5 mg caffeine</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ circulating lymphocytes and Treg cells<break></break>
↓ IL-10 and TGF-β</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B108-ijms-20-01714" ref-type="bibr">108</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Healthy subjects, 1 g/day, 4 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ circulating Treg cells (CD3<sup>+</sup>
CD4<sup>+</sup>
CD25<sup>+</sup>
CD127<sup>dim/neg</sup>
)<break></break>
↑ γδ<sup>+</sup>
NKG2D<sup>+</sup>
T cell<break></break>
↑ CD3<sup>−</sup>
CD56<sup>+</sup>
NKG2D<sup>+</sup>
NK<break></break>
↔ CD8, CD4, CD19<break></break>
↓ TNF-α, MCP-1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B104-ijms-20-01714" ref-type="bibr">104</xref>
]</td>
</tr>
<tr><td rowspan="7" align="center" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" colspan="1">MOUSE</td>
<td rowspan="7" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CYTOKINES</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CA</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Swiss albino bearing Ehrlich ascites tumor (EAT) cells</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ IL-2, IL-12, IFN-γ<break></break>
↓ IL-4 and IL-10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B84-ijms-20-01714" ref-type="bibr">84</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing mammary cancer cells (EMT6/P) s.c.,<break></break>
Met 100 µL 80 mg/kg i.p. + CUR 100 µL 50 mg/kg p.o.</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ IFN-γ, IL-4<break></break>
↔ IL-2, IL-10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B110-ijms-20-01714" ref-type="bibr">110</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing melanoma cells (B16F10) s.c., treated with CUR-PEG and LCP Trp2-based vaccine</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-6, CCL2 in tumor microenvironment<break></break>
↑ TNF-α, IFN-γ in tumor microenvironment<break></break>
↑ CTL response</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B95-ijms-20-01714" ref-type="bibr">95</xref>
]</td>
</tr>
<tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">P2Et</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing melanoma cells (B16F10) s.c., 75 mg/kg, i.p. twice/week/10 days + s.c. twice/week/21 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ TNF-α, IL-6<break></break>
↓ IL-17, IL-4</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing mammary cancer cells (4T1) s.c., 75 mg/kg, i.p. twice/week/10 days + s.c. twice/week/32 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ TNF-α, IL-6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 Healthy, 75 mg/kg i.p., twice/week/3 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ IL-10, IL-17, IFN-γ, IL-6, IL-4, IL-2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c Healthy,75 mg/kg i.p., twice/week/5 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ IFN-γ, IL-6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-ijms-20-01714" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin;background:#A6A6A6" colspan="1">HUMAN</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CYTOKINES</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ healthy subject, 5 g, orally administered</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ Kynurenin/tryptophan ratio as measure of IDO activity</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B90-ijms-20-01714" ref-type="bibr">90</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGCG</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate cancer cells (PC3, DU145, LnCap), pre-treated EGCG 40 µg/mL, 24 h and then transfected with CpG-ODN 1 µM, 6 or 24 h</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ IL-6, IL-8, CXCL-1, IP-10, CCL-5, TGF-β1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B111-ijms-20-01714" ref-type="bibr">111</xref>
]</td>
</tr>
<tr><td rowspan="6" align="center" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" colspan="1">MOUSE</td>
<td rowspan="6" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">ENDOTHELIAL CELLS</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CA</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♂ Swiss albino bearing Ehrlich ascites tumor (EAT) cells</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ neovascularization<break></break>
↓ reduced microvessel density<break></break>
↓ VEGF release in ascite</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B84-ijms-20-01714" ref-type="bibr">84</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing melanoma cells (B16F10) s.c., treated with CUR-PEG and LCP Trp2-based vaccine</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ tumor vessels<break></break>
↓ TAF</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B95-ijms-20-01714" ref-type="bibr">95</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">P2Et</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma cells (B16F10), P2Et 1.9–250 µg/mL</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ ICD, ↑autophagy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B92-ijms-20-01714" ref-type="bibr">92</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">RES</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C3/HeN or C3/HeJ (TLR4 mutated) bearing skin cancer DMBA-induced, 10 µmol/mouse, topically applied 1h before DMBA</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ IFN-γ<sup>+</sup>
(skin lysates)<break></break>
↑ IL-12 (skin lysates)<break></break>
↓ MMP-2 MMP-9<break></break>
↓ VEGF (skin lysates)<break></break>
↓ CD31 in tumor</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B112-ijms-20-01714" ref-type="bibr">112</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing melanoma cells (B16F10) s.c. or i.v., HDIL-2 75.000 U, 3 times/day/3 days + RES 100 mg/kg p.o., 5 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ vascular leak syndrome</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B113-ijms-20-01714" ref-type="bibr">113</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ Balb/c bearing renal carcinoma cells (RENCA) cells, i.p. 1–5 mg/kg</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ IFN-γ, Fas<break></break>
↓ IL-6, IL-10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B93-ijms-20-01714" ref-type="bibr">93</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin;background:#A6A6A6" colspan="1">HUMAN</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">ENDOTHELIAL CELLS</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">A009</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Human umbilical vein endothelial cells (HUVEC)</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ proliferation<break></break>
↓ angiogenesis<break></break>
↓ migration</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B114-ijms-20-01714" ref-type="bibr">114</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colon cancer cells (HT-29, HCT-116);Prostate cancer cells (PC-3, DU-145, LNCaP)</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ VEGF, IL-8 CXCL8, CXCL12<break></break>
↓ proliferation<break></break>
↓ angiogenesis<break></break>
↓ migration</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B115-ijms-20-01714" ref-type="bibr">115</xref>
,<xref rid="B116-ijms-20-01714" ref-type="bibr">116</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" colspan="1">MOUSE</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">IMMUNE CHECKPOINT</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">APG or CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing melanoma cells (B16F10) s.c., CUR 50 mg/kg or APG 150 mg/kg, p.o., 12 days</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ PD-L1<break></break>
↑ CD4<sup>+</sup>
CD8<sup>+</sup>
in tumor microenvironment</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B117-ijms-20-01714" ref-type="bibr">117</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGCG or GTE</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma cells (B16F10) co-culture with tumor specific T cells, EGCG 30 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ A/J mice bearing lung cancer NNK-induced; GTE 0.3% in drinking water</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ PD-L1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B119-ijms-20-01714" ref-type="bibr">119</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BDMC</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">♀ C57BL/6 bearing bladder cancer cells (MB49) s.c./i.v. treated with Anti-PD-L1 Ab + BDMC 3 mg/kg, 4/2 weeks</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ CD8<sup>+</sup>
(SPL and LN)<break></break>
↑ IFN-γ, granzyme B<break></break>
↓ PD-1<break></break>
↑ survival</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B120-ijms-20-01714" ref-type="bibr">120</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin;background:#A6A6A6" colspan="1">HUMAN</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">IMMUNE CHECKPOINT</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">APG or CUR</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma cell lines (A375, A2058, RPMI-7951) treated APG 5–60 µM or CUR 5–30 µM, 24 h; Jurkat cell-mediated A375 killing assays</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ PD-L1<break></break>
↓ p-STAT1<break></break>
↑ CD8 citotoxicity<break></break>
↑ IL-2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B117-ijms-20-01714" ref-type="bibr">117</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RES or Pic</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast cancer cells (Cal51, BT549, BT474) and Colon cancer cells (SKBR3, HCT116, SW480, HT29 and SW620)RES 50 µM, Pic 50 µM</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ PD-L1<break></break>
↑ DNA damage</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B118-ijms-20-01714" ref-type="bibr">118</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGCG or GTE</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung cancer cells (A549, H1299, Lu99), 50–100 µg/mL</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ PD-L1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B119-ijms-20-01714" ref-type="bibr">119</xref>
]</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>Abbreviations: i.c., intracranial; s.c., subcutaneous; i.p., intraperitoneal; i.t., intratumoral; p.t., peritumoral; p.o. per os; i.v. intra venous; LN, lymph node; SPL, spleen; NO, nitric oxide; LPS, Lipopolysaccharide; ROS, reactive oxygen species; ConA, Concanavalin A; Ab, antibody; CTL, cytotoxic T lymphocyte; DMBA, Dimethylbenzathracene; Met, Metformin; 4NQO, 4-nitroquinoline-oxide-induced; CQ, Chloroquine.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Bei, Roberto" sort="Bei, Roberto" uniqKey="Bei R" first="Roberto" last="Bei">Roberto Bei</name>
<name sortKey="Benvenuto, Monica" sort="Benvenuto, Monica" uniqKey="Benvenuto M" first="Monica" last="Benvenuto">Monica Benvenuto</name>
<name sortKey="Ciuffa, Sara" sort="Ciuffa, Sara" uniqKey="Ciuffa S" first="Sara" last="Ciuffa">Sara Ciuffa</name>
<name sortKey="Fazi, Sara" sort="Fazi, Sara" uniqKey="Fazi S" first="Sara" last="Fazi">Sara Fazi</name>
<name sortKey="Focaccetti, Chiara" sort="Focaccetti, Chiara" uniqKey="Focaccetti C" first="Chiara" last="Focaccetti">Chiara Focaccetti</name>
<name sortKey="Giganti, Maria Gabriella" sort="Giganti, Maria Gabriella" uniqKey="Giganti M" first="Maria Gabriella" last="Giganti">Maria Gabriella Giganti</name>
<name sortKey="Izzi, Valerio" sort="Izzi, Valerio" uniqKey="Izzi V" first="Valerio" last="Izzi">Valerio Izzi</name>
<name sortKey="Manzari, Vittorio" sort="Manzari, Vittorio" uniqKey="Manzari V" first="Vittorio" last="Manzari">Vittorio Manzari</name>
<name sortKey="Modesti, Andrea" sort="Modesti, Andrea" uniqKey="Modesti A" first="Andrea" last="Modesti">Andrea Modesti</name>
<name sortKey="Potenza, Vito" sort="Potenza, Vito" uniqKey="Potenza V" first="Vito" last="Potenza">Vito Potenza</name>
</noCountry>
</tree>
</affiliations>
</record>
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