RapamycinFungusV1, Main, Exploration, bibRecord, 000A02

Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.

Identifieur interne : 000A02 ( Main/Exploration ); précédent : 000A01; suivant : 000A03

Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.

Auteurs : Peter J. Siska [États-Unis] ; Gerritje J W. Van Der Windt [Pays-Bas] ; Rigel J. Kishton [États-Unis] ; Sivan Cohen [États-Unis] ; William Eisner [États-Unis] ; Nancie J. Maciver [États-Unis] ; Arnon P. Kater [Pays-Bas] ; J Brice Weinberg [États-Unis] ; Jeffrey C. Rathmell [États-Unis]

Source :

Journal of immunology (Baltimore, Md. : 1950) [ 1550-6606 ] ; 2016.

RBID : pubmed:27511728

Descripteurs français

KwdFr :
- Activation des lymphocytes (MeSH), Animaux (MeSH), Complexe-1 cible mécanistique de la rapamycine (MeSH), Complexes multiprotéiques (métabolisme), Glucose (antagonistes et inhibiteurs), Glucose (métabolisme), Glycolyse (MeSH), Humains (MeSH), Leucémie chronique lymphocytaire à cellules B (immunologie), Lignée cellulaire tumorale (MeSH), Lymphocytes T (immunologie), Métabolisme glucidique (MeSH), Protéines proto-oncogènes c-akt (métabolisme), Rate (cytologie), Rate (immunologie), Souris (MeSH), Sérine-thréonine kinases TOR (métabolisme), Transduction du signal (MeSH), Transporteur de glucose de type 1 (antagonistes et inhibiteurs), Transporteur de glucose de type 1 (génétique).
MESH :
- antagonistes et inhibiteurs : Glucose, Transporteur de glucose de type 1.
- cytologie : Rate.
- génétique : Transporteur de glucose de type 1.
- immunologie : Leucémie chronique lymphocytaire à cellules B, Lymphocytes T, Rate.
- métabolisme : Complexes multiprotéiques, Glucose, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- Activation des lymphocytes, Animaux, Complexe-1 cible mécanistique de la rapamycine, Glycolyse, Humains, Lignée cellulaire tumorale, Métabolisme glucidique, Souris, Transduction du signal.

English descriptors

KwdEn :
- Animals (MeSH), Carbohydrate Metabolism (MeSH), Cell Line, Tumor (MeSH), Glucose (antagonists & inhibitors), Glucose (metabolism), Glucose Transporter Type 1 (antagonists & inhibitors), Glucose Transporter Type 1 (genetics), Glycolysis (MeSH), Humans (MeSH), Leukemia, Lymphocytic, Chronic, B-Cell (immunology), Lymphocyte Activation (MeSH), Mechanistic Target of Rapamycin Complex 1 (MeSH), Mice (MeSH), Multiprotein Complexes (metabolism), Proto-Oncogene Proteins c-akt (metabolism), Signal Transduction (MeSH), Spleen (cytology), Spleen (immunology), T-Lymphocytes (immunology), TOR Serine-Threonine Kinases (metabolism).
MESH :
- chemical , antagonists & inhibitors : Glucose, Glucose Transporter Type 1.
- chemical , genetics : Glucose Transporter Type 1.
- chemical , metabolism : Glucose, Multiprotein Complexes, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- cytology : Spleen.
- immunology : Leukemia, Lymphocytic, Chronic, B-Cell, Spleen, T-Lymphocytes.
- Animals, Carbohydrate Metabolism, Cell Line, Tumor, Glycolysis, Humans, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Mice, Signal Transduction.

Abstract

Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction.

DOI: 10.4049/jimmunol.1502464
PubMed: 27511728
PubMed Central: PMC5010978

Affiliations:

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Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Carbohydrate Metabolism (MeSH)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Glucose (antagonists & inhibitors)</term>
<term>Glucose (metabolism)</term>
<term>Glucose Transporter Type 1 (antagonists & inhibitors)</term>
<term>Glucose Transporter Type 1 (genetics)</term>
<term>Glycolysis (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Leukemia, Lymphocytic, Chronic, B-Cell (immunology)</term>
<term>Lymphocyte Activation (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term>
<term>Mice (MeSH)</term>
<term>Multiprotein Complexes (metabolism)</term>
<term>Proto-Oncogene Proteins c-akt (metabolism)</term>
<term>Signal Transduction (MeSH)</term>
<term>Spleen (cytology)</term>
<term>Spleen (immunology)</term>
<term>T-Lymphocytes (immunology)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Activation des lymphocytes (MeSH)</term>
<term>Animaux (MeSH)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term>
<term>Complexes multiprotéiques (métabolisme)</term>
<term>Glucose (antagonistes et inhibiteurs)</term>
<term>Glucose (métabolisme)</term>
<term>Glycolyse (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Leucémie chronique lymphocytaire à cellules B (immunologie)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Lymphocytes T (immunologie)</term>
<term>Métabolisme glucidique (MeSH)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Rate (cytologie)</term>
<term>Rate (immunologie)</term>
<term>Souris (MeSH)</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Transduction du signal (MeSH)</term>
<term>Transporteur de glucose de type 1 (antagonistes et inhibiteurs)</term>
<term>Transporteur de glucose de type 1 (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Glucose</term>
<term>Glucose Transporter Type 1</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Glucose Transporter Type 1</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glucose</term>
<term>Multiprotein Complexes</term>
<term>Proto-Oncogene Proteins c-akt</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Glucose</term>
<term>Transporteur de glucose de type 1</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Rate</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Spleen</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Transporteur de glucose de type 1</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Leucémie chronique lymphocytaire à cellules B</term>
<term>Lymphocytes T</term>
<term>Rate</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Leukemia, Lymphocytic, Chronic, B-Cell</term>
<term>Spleen</term>
<term>T-Lymphocytes</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexes multiprotéiques</term>
<term>Glucose</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Carbohydrate Metabolism</term>
<term>Cell Line, Tumor</term>
<term>Glycolysis</term>
<term>Humans</term>
<term>Lymphocyte Activation</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Mice</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Activation des lymphocytes</term>
<term>Animaux</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Glycolyse</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Métabolisme glucidique</term>
<term>Souris</term>
<term>Transduction du signal</term>
</keywords>
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<front><div type="abstract" xml:lang="en">Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction.</div>
</front>
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<DateCompleted><Year>2017</Year>
<Month>08</Month>
<Day>14</Day>
</DateCompleted>
<DateRevised><Year>2018</Year>
<Month>11</Month>
<Day>13</Day>
</DateRevised>
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<JournalIssue CitedMedium="Internet"><Volume>197</Volume>
<Issue>6</Issue>
<PubDate><Year>2016</Year>
<Month>09</Month>
<Day>15</Day>
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<Title>Journal of immunology (Baltimore, Md. : 1950)</Title>
<ISOAbbreviation>J Immunol</ISOAbbreviation>
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<ArticleTitle>Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.</ArticleTitle>
<Pagination><MedlinePgn>2532-40</MedlinePgn>
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<Abstract><AbstractText>Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction.</AbstractText>
<CopyrightInformation>Copyright © 2016 by The American Association of Immunologists, Inc.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Siska</LastName>
<ForeName>Peter J</ForeName>
<Initials>PJ</Initials>
<Identifier Source="ORCID">0000-0002-1521-6213</Identifier>
<AffiliationInfo><Affiliation>Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>van der Windt</LastName>
<ForeName>Gerritje J W</ForeName>
<Initials>GJ</Initials>
<AffiliationInfo><Affiliation>Department of Experimental Immunology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kishton</LastName>
<ForeName>Rigel J</ForeName>
<Initials>RJ</Initials>
<Identifier Source="ORCID">0000-0002-5682-3896</Identifier>
<AffiliationInfo><Affiliation>Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cohen</LastName>
<ForeName>Sivan</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Eisner</LastName>
<ForeName>William</ForeName>
<Initials>W</Initials>
<AffiliationInfo><Affiliation>Department of Pediatrics, Duke University, Durham, NC 27710;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>MacIver</LastName>
<ForeName>Nancie J</ForeName>
<Initials>NJ</Initials>
<Identifier Source="ORCID">0000-0003-3676-9391</Identifier>
<AffiliationInfo><Affiliation>Department of Pediatrics, Duke University, Durham, NC 27710;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kater</LastName>
<ForeName>Arnon P</ForeName>
<Initials>AP</Initials>
<Identifier Source="ORCID">0000-0003-3190-1891</Identifier>
<AffiliationInfo><Affiliation>Department of Hematology, Academic Medical Center, 1100 DD Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam, 1105 AZ Amsterdam, the Netherlands;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Weinberg</LastName>
<ForeName>J Brice</ForeName>
<Initials>JB</Initials>
<Identifier Source="ORCID">0000-0003-4052-5576</Identifier>
<AffiliationInfo><Affiliation>Department of Medicine, Duke University, Durham, NC 27708; and Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC 27705.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rathmell</LastName>
<ForeName>Jeffrey C</ForeName>
<Initials>JC</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232; jeff.rathmell@vanderbilt.edu.</Affiliation>
</AffiliationInfo>
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</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>F31 CA183529</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 DK105550</GrantID>
<Acronym>DK</Acronym>
<Agency>NIDDK NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 DK106090</GrantID>
<Acronym>DK</Acronym>
<Agency>NIDDK NIH HHS</Agency>
<Country>United States</Country>
</Grant>
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<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
<PublicationType UI="D013486">Research Support, U.S. Gov't, Non-P.H.S.</PublicationType>
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<ArticleDate DateType="Electronic"><Year>2016</Year>
<Month>08</Month>
<Day>10</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>J Immunol</MedlineTA>
<NlmUniqueID>2985117R</NlmUniqueID>
<ISSNLinking>0022-1767</ISSNLinking>
</MedlineJournalInfo>
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</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D046912">Multiprotein Complexes</NameOfSubstance>
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<Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber>
<NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance>
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<Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance>
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<Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D051057">Proto-Oncogene Proteins c-akt</NameOfSubstance>
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<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D050260" MajorTopicYN="N">Carbohydrate Metabolism</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005947" MajorTopicYN="N">Glucose</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
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<MeshHeading><DescriptorName UI="D008213" MajorTopicYN="N">Lymphocyte Activation</DescriptorName>
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<MeshHeading><DescriptorName UI="D015398" MajorTopicYN="Y">Signal Transduction</DescriptorName>
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<MeshHeading><DescriptorName UI="D013154" MajorTopicYN="N">Spleen</DescriptorName>
<QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
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<MeshHeading><DescriptorName UI="D013601" MajorTopicYN="N">T-Lymphocytes</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
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<CoiStatement>The authors have no conflicts of interest to declare</CoiStatement>
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Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.

Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.

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