Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment.
Identifieur interne : 000858 ( Main/Exploration ); précédent : 000857; suivant : 000859Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment.
Auteurs : Michael Fehlings [Singapour] ; Suchit Jhunjhunwala [États-Unis] ; Marcin Kowanetz [États-Unis] ; William E. O'Gorman [États-Unis] ; Priti S. Hegde [États-Unis] ; Hermi Sumatoh [Singapour] ; Boon Heng Lee [Singapour] ; Alessandra Nardin [Singapour] ; Etienne Becht [Singapour] ; Susan Flynn [États-Unis] ; Marcus Ballinger [Singapour] ; Evan W. Newell [Singapour] ; Mahesh Yadav [États-Unis]Source :
- Journal for immunotherapy of cancer [ 2051-1426 ] ; 2019.
Descripteurs français
- KwdFr :
- Adulte d'âge moyen (MeSH), Anticorps monoclonaux humanisés (pharmacologie), Anticorps monoclonaux humanisés (usage thérapeutique), Antigène CD274 (antagonistes et inhibiteurs), Antigène CD274 (immunologie), Antigènes néoplasiques (génétique), Antigènes néoplasiques (isolement et purification), Antigènes néoplasiques (métabolisme), Antinéoplasiques immunologiques (pharmacologie), Antinéoplasiques immunologiques (usage thérapeutique), Carcinome pulmonaire non à petites cellules (génétique), Carcinome pulmonaire non à petites cellules (immunologie), Carcinome pulmonaire non à petites cellules (sang), Carcinome pulmonaire non à petites cellules (traitement médicamenteux), Femelle (MeSH), Humains (MeSH), Lymphocytes T CD8+ (immunologie), Lymphocytes T CD8+ (métabolisme), Mutation (MeSH), Mâle (MeSH), Sujet âgé (MeSH), Surveillance des médicaments (méthodes), Séquençage de l'exome entier (MeSH), Tumeurs du poumon (génétique), Tumeurs du poumon (immunologie), Tumeurs du poumon (sang), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- antagonistes et inhibiteurs : Antigène CD274.
- génétique : Antigènes néoplasiques, Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- immunologie : Antigène CD274, Carcinome pulmonaire non à petites cellules, Lymphocytes T CD8+, Tumeurs du poumon.
- isolement et purification : Antigènes néoplasiques.
- métabolisme : Antigènes néoplasiques, Lymphocytes T CD8+.
- méthodes : Surveillance des médicaments.
- pharmacologie : Anticorps monoclonaux humanisés, Antinéoplasiques immunologiques.
- sang : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- traitement médicamenteux : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- usage thérapeutique : Anticorps monoclonaux humanisés, Antinéoplasiques immunologiques.
- Adulte d'âge moyen, Femelle, Humains, Mutation, Mâle, Sujet âgé, Séquençage de l'exome entier.
English descriptors
- KwdEn :
- Aged (MeSH), Antibodies, Monoclonal, Humanized (pharmacology), Antibodies, Monoclonal, Humanized (therapeutic use), Antigens, Neoplasm (genetics), Antigens, Neoplasm (isolation & purification), Antigens, Neoplasm (metabolism), Antineoplastic Agents, Immunological (pharmacology), Antineoplastic Agents, Immunological (therapeutic use), B7-H1 Antigen (antagonists & inhibitors), B7-H1 Antigen (immunology), CD8-Positive T-Lymphocytes (immunology), CD8-Positive T-Lymphocytes (metabolism), Carcinoma, Non-Small-Cell Lung (blood), Carcinoma, Non-Small-Cell Lung (drug therapy), Carcinoma, Non-Small-Cell Lung (genetics), Carcinoma, Non-Small-Cell Lung (immunology), Drug Monitoring (methods), Female (MeSH), Humans (MeSH), Lung Neoplasms (blood), Lung Neoplasms (drug therapy), Lung Neoplasms (genetics), Lung Neoplasms (immunology), Male (MeSH), Middle Aged (MeSH), Mutation (MeSH), RNA-Seq (MeSH), Whole Exome Sequencing (MeSH).
- MESH :
- chemical , antagonists & inhibitors : B7-H1 Antigen.
- chemical , genetics : Antigens, Neoplasm.
- chemical , immunology : B7-H1 Antigen.
- chemical , isolation & purification : Antigens, Neoplasm.
- chemical , metabolism : Antigens, Neoplasm.
- chemical , pharmacology : Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological.
- chemical , therapeutic use : Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological.
- blood : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- drug therapy : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- genetics : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- immunology : CD8-Positive T-Lymphocytes, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- metabolism : CD8-Positive T-Lymphocytes.
- methods : Drug Monitoring.
- Aged, Female, Humans, Male, Middle Aged, Mutation, RNA-Seq, Whole Exome Sequencing.
Abstract
BACKGROUND
There is strong evidence that immunotherapy-mediated tumor rejection can be driven by tumor-specific CD8+ T cells reinvigorated to recognize neoantigens derived from tumor somatic mutations. Thus, the frequencies or characteristics of tumor-reactive, mutation-specific CD8+ T cells could be used as biomarkers of an anti-tumor response. However, such neoantigen-specific T cells are difficult to reliably identify due to their low frequency in peripheral blood and wide range of potential epitope specificities.
METHODS
Peripheral blood mononuclear cells (PBMC) from 14 non-small cell lung cancer (NSCLC) patients were collected pre- and post-treatment with the anti-PD-L1 antibody atezolizumab. Using whole exome sequencing and RNA sequencing we identified tumor neoantigens that are predicted to bind to major histocompatibility complex class I (MHC-I) and utilized mass cytometry, together with cellular 'barcoding', to profile immune cells from patients with objective response to therapy (n = 8) and those with progressive disease (n = 6). In parallel, a highly-multiplexed combinatorial tetramer staining was used to screen antigen-specific CD8+ T cells in peripheral blood for 782 candidate tumor neoantigens and 71 known viral-derived control peptide epitopes across all patient samples.
RESULTS
No significant treatment- or response associated phenotypic difference were measured in bulk CD8+ T cells. Multiplexed peptide-MHC multimer staining detected 20 different neoantigen-specific T cell populations, as well as T cells specific for viral control antigens. Not only were neoantigen-specific T cells more frequently detected in responding patients, their phenotypes were also almost entirely distinct. Neoantigen-specific T cells from responder patients typically showed a differentiated effector phenotype, most like Cytomegalovirus (CMV) and some types of Epstein-Barr virus (EBV)-specific CD8+ T cells. In contrast, more memory-like phenotypic profiles were observed for neoantigen-specific CD8+ T cells from patients with progressive disease.
CONCLUSION
This study demonstrates that neoantigen-specific T cells can be detected in peripheral blood in non-small cell lung cancer (NSCLC) patients during anti-PD-L1 therapy. Patients with an objective response had an enrichment of neoantigen-reactive T cells and these cells showed a phenotype that differed from patients without a response. These findings suggest the ex vivo identification, characterization, and longitudinal follow-up of rare tumor-specific differentiated effector neoantigen-specific T cells may be useful in predicting response to checkpoint blockade.
TRIAL REGISTRATION
POPLAR trial NCT01903993 .
DOI: 10.1186/s40425-019-0695-9
PubMed: 31511069
PubMed Central: PMC6740011
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
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Newell</name><affiliation wicri:level="1"><nlm:affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>immunoSCAPE Pte Ltd, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Yadav, Mahesh" sort="Yadav, Mahesh" uniqKey="Yadav M" first="Mahesh" last="Yadav">Mahesh Yadav</name><affiliation wicri:level="1"><nlm:affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. yadav.mahesh@gene.com.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech, 1 DNA way, South San Francisco, CA, 94080</wicri:regionArea><wicri:noRegion>94080</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31511069</idno><idno type="pmid">31511069</idno><idno type="doi">10.1186/s40425-019-0695-9</idno><idno type="pmc">PMC6740011</idno><idno type="wicri:Area/Main/Corpus">000714</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000714</idno><idno type="wicri:Area/Main/Curation">000714</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000714</idno><idno type="wicri:Area/Main/Exploration">000714</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment.</title><author><name sortKey="Fehlings, Michael" sort="Fehlings, Michael" uniqKey="Fehlings M" first="Michael" last="Fehlings">Michael Fehlings</name><affiliation wicri:level="1"><nlm:affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>immunoSCAPE Pte Ltd, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Jhunjhunwala, Suchit" sort="Jhunjhunwala, Suchit" uniqKey="Jhunjhunwala S" first="Suchit" last="Jhunjhunwala">Suchit Jhunjhunwala</name><affiliation wicri:level="1"><nlm:affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech, 1 DNA way, South San Francisco, CA, 94080</wicri:regionArea><wicri:noRegion>94080</wicri:noRegion></affiliation></author><author><name sortKey="Kowanetz, Marcin" sort="Kowanetz, Marcin" uniqKey="Kowanetz M" first="Marcin" last="Kowanetz">Marcin Kowanetz</name><affiliation wicri:level="1"><nlm:affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech, 1 DNA way, South San Francisco, CA, 94080</wicri:regionArea><wicri:noRegion>94080</wicri:noRegion></affiliation></author><author><name sortKey="O Gorman, William E" sort="O Gorman, William E" uniqKey="O Gorman W" first="William E" last="O'Gorman">William E. O'Gorman</name><affiliation wicri:level="1"><nlm:affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech, 1 DNA way, South San Francisco, CA, 94080</wicri:regionArea><wicri:noRegion>94080</wicri:noRegion></affiliation></author><author><name sortKey="Hegde, Priti S" sort="Hegde, Priti S" uniqKey="Hegde P" first="Priti S" last="Hegde">Priti S. Hegde</name><affiliation wicri:level="1"><nlm:affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech, 1 DNA way, South San Francisco, CA, 94080</wicri:regionArea><wicri:noRegion>94080</wicri:noRegion></affiliation></author><author><name sortKey="Sumatoh, Hermi" sort="Sumatoh, Hermi" uniqKey="Sumatoh H" first="Hermi" last="Sumatoh">Hermi Sumatoh</name><affiliation wicri:level="1"><nlm:affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>immunoSCAPE Pte Ltd, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Boon Heng" sort="Lee, Boon Heng" uniqKey="Lee B" first="Boon Heng" last="Lee">Boon Heng Lee</name><affiliation wicri:level="1"><nlm:affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>immunoSCAPE Pte Ltd, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Nardin, Alessandra" sort="Nardin, Alessandra" uniqKey="Nardin A" first="Alessandra" last="Nardin">Alessandra Nardin</name><affiliation wicri:level="1"><nlm:affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>immunoSCAPE Pte Ltd, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Becht, Etienne" sort="Becht, Etienne" uniqKey="Becht E" first="Etienne" last="Becht">Etienne Becht</name><affiliation wicri:level="1"><nlm:affiliation>Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Flynn, Susan" sort="Flynn, Susan" uniqKey="Flynn S" first="Susan" last="Flynn">Susan Flynn</name><affiliation wicri:level="1"><nlm:affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech, 1 DNA way, South San Francisco, CA, 94080</wicri:regionArea><wicri:noRegion>94080</wicri:noRegion></affiliation></author><author><name sortKey="Ballinger, Marcus" sort="Ballinger, Marcus" uniqKey="Ballinger M" first="Marcus" last="Ballinger">Marcus Ballinger</name><affiliation wicri:level="1"><nlm:affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>immunoSCAPE Pte Ltd, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Newell, Evan W" sort="Newell, Evan W" uniqKey="Newell E" first="Evan W" last="Newell">Evan W. Newell</name><affiliation wicri:level="1"><nlm:affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>immunoSCAPE Pte Ltd, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Yadav, Mahesh" sort="Yadav, Mahesh" uniqKey="Yadav M" first="Mahesh" last="Yadav">Mahesh Yadav</name><affiliation wicri:level="1"><nlm:affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. yadav.mahesh@gene.com.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech, 1 DNA way, South San Francisco, CA, 94080</wicri:regionArea><wicri:noRegion>94080</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal for immunotherapy of cancer</title><idno type="eISSN">2051-1426</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged (MeSH)</term><term>Antibodies, Monoclonal, Humanized (pharmacology)</term><term>Antibodies, Monoclonal, Humanized (therapeutic use)</term><term>Antigens, Neoplasm (genetics)</term><term>Antigens, Neoplasm (isolation & purification)</term><term>Antigens, Neoplasm (metabolism)</term><term>Antineoplastic Agents, Immunological (pharmacology)</term><term>Antineoplastic Agents, Immunological (therapeutic use)</term><term>B7-H1 Antigen (antagonists & inhibitors)</term><term>B7-H1 Antigen (immunology)</term><term>CD8-Positive T-Lymphocytes (immunology)</term><term>CD8-Positive T-Lymphocytes (metabolism)</term><term>Carcinoma, Non-Small-Cell Lung (blood)</term><term>Carcinoma, Non-Small-Cell Lung (drug therapy)</term><term>Carcinoma, Non-Small-Cell Lung (genetics)</term><term>Carcinoma, Non-Small-Cell Lung (immunology)</term><term>Drug Monitoring (methods)</term><term>Female (MeSH)</term><term>Humans (MeSH)</term><term>Lung Neoplasms (blood)</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (genetics)</term><term>Lung Neoplasms (immunology)</term><term>Male (MeSH)</term><term>Middle Aged (MeSH)</term><term>Mutation (MeSH)</term><term>RNA-Seq (MeSH)</term><term>Whole Exome Sequencing (MeSH)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte d'âge moyen (MeSH)</term><term>Anticorps monoclonaux humanisés (pharmacologie)</term><term>Anticorps monoclonaux humanisés (usage thérapeutique)</term><term>Antigène CD274 (antagonistes et inhibiteurs)</term><term>Antigène CD274 (immunologie)</term><term>Antigènes néoplasiques (génétique)</term><term>Antigènes néoplasiques (isolement et purification)</term><term>Antigènes néoplasiques (métabolisme)</term><term>Antinéoplasiques immunologiques (pharmacologie)</term><term>Antinéoplasiques immunologiques (usage thérapeutique)</term><term>Carcinome pulmonaire non à petites cellules (génétique)</term><term>Carcinome pulmonaire non à petites cellules (immunologie)</term><term>Carcinome pulmonaire non à petites cellules (sang)</term><term>Carcinome pulmonaire non à petites cellules (traitement médicamenteux)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Lymphocytes T CD8+ (immunologie)</term><term>Lymphocytes T CD8+ (métabolisme)</term><term>Mutation (MeSH)</term><term>Mâle (MeSH)</term><term>Sujet âgé (MeSH)</term><term>Surveillance des médicaments (méthodes)</term><term>Séquençage de l'exome entier (MeSH)</term><term>Tumeurs du poumon (génétique)</term><term>Tumeurs du poumon (immunologie)</term><term>Tumeurs du poumon (sang)</term><term>Tumeurs du poumon (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>B7-H1 Antigen</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antigens, Neoplasm</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>B7-H1 Antigen</term></keywords><keywords scheme="MESH" type="chemical" qualifier="isolation & purification" xml:lang="en"><term>Antigens, Neoplasm</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antigens, Neoplasm</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antibodies, Monoclonal, Humanized</term><term>Antineoplastic Agents, Immunological</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antibodies, Monoclonal, Humanized</term><term>Antineoplastic Agents, Immunological</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Antigène CD274</term></keywords><keywords scheme="MESH" qualifier="blood" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Antigènes néoplasiques</term><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Antigène CD274</term><term>Carcinome pulmonaire non à petites cellules</term><term>Lymphocytes T CD8+</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>CD8-Positive T-Lymphocytes</term><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="isolement et purification" xml:lang="fr"><term>Antigènes néoplasiques</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>CD8-Positive T-Lymphocytes</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Drug Monitoring</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antigènes néoplasiques</term><term>Lymphocytes T CD8+</term></keywords><keywords scheme="MESH" qualifier="méthodes" xml:lang="fr"><term>Surveillance des médicaments</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Anticorps monoclonaux humanisés</term><term>Antinéoplasiques immunologiques</term></keywords><keywords scheme="MESH" qualifier="sang" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Anticorps monoclonaux humanisés</term><term>Antinéoplasiques immunologiques</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Aged</term><term>Female</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Mutation</term><term>RNA-Seq</term><term>Whole Exome Sequencing</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte d'âge moyen</term><term>Femelle</term><term>Humains</term><term>Mutation</term><term>Mâle</term><term>Sujet âgé</term><term>Séquençage de l'exome entier</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>There is strong evidence that immunotherapy-mediated tumor rejection can be driven by tumor-specific CD8+ T cells reinvigorated to recognize neoantigens derived from tumor somatic mutations. Thus, the frequencies or characteristics of tumor-reactive, mutation-specific CD8+ T cells could be used as biomarkers of an anti-tumor response. However, such neoantigen-specific T cells are difficult to reliably identify due to their low frequency in peripheral blood and wide range of potential epitope specificities.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>Peripheral blood mononuclear cells (PBMC) from 14 non-small cell lung cancer (NSCLC) patients were collected pre- and post-treatment with the anti-PD-L1 antibody atezolizumab. Using whole exome sequencing and RNA sequencing we identified tumor neoantigens that are predicted to bind to major histocompatibility complex class I (MHC-I) and utilized mass cytometry, together with cellular 'barcoding', to profile immune cells from patients with objective response to therapy (n = 8) and those with progressive disease (n = 6). In parallel, a highly-multiplexed combinatorial tetramer staining was used to screen antigen-specific CD8+ T cells in peripheral blood for 782 candidate tumor neoantigens and 71 known viral-derived control peptide epitopes across all patient samples.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>No significant treatment- or response associated phenotypic difference were measured in bulk CD8+ T cells. Multiplexed peptide-MHC multimer staining detected 20 different neoantigen-specific T cell populations, as well as T cells specific for viral control antigens. Not only were neoantigen-specific T cells more frequently detected in responding patients, their phenotypes were also almost entirely distinct. Neoantigen-specific T cells from responder patients typically showed a differentiated effector phenotype, most like Cytomegalovirus (CMV) and some types of Epstein-Barr virus (EBV)-specific CD8+ T cells. In contrast, more memory-like phenotypic profiles were observed for neoantigen-specific CD8+ T cells from patients with progressive disease.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSION</b></p><p>This study demonstrates that neoantigen-specific T cells can be detected in peripheral blood in non-small cell lung cancer (NSCLC) patients during anti-PD-L1 therapy. Patients with an objective response had an enrichment of neoantigen-reactive T cells and these cells showed a phenotype that differed from patients without a response. These findings suggest the ex vivo identification, characterization, and longitudinal follow-up of rare tumor-specific differentiated effector neoantigen-specific T cells may be useful in predicting response to checkpoint blockade.</p></div><div type="abstract" xml:lang="en"><p><b>TRIAL REGISTRATION</b></p><p>POPLAR trial NCT01903993 .</p></div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31511069</PMID><DateCompleted><Year>2020</Year><Month>08</Month><Day>03</Day></DateCompleted><DateRevised><Year>2020</Year><Month>08</Month><Day>03</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2051-1426</ISSN><JournalIssue CitedMedium="Internet"><Volume>7</Volume><Issue>1</Issue><PubDate><Year>2019</Year><Month>09</Month><Day>12</Day></PubDate></JournalIssue><Title>Journal for immunotherapy of cancer</Title><ISOAbbreviation>J Immunother Cancer</ISOAbbreviation></Journal><ArticleTitle>Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment.</ArticleTitle><Pagination><MedlinePgn>249</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1186/s40425-019-0695-9</ELocationID><Abstract><AbstractText Label="BACKGROUND">There is strong evidence that immunotherapy-mediated tumor rejection can be driven by tumor-specific CD8+ T cells reinvigorated to recognize neoantigens derived from tumor somatic mutations. Thus, the frequencies or characteristics of tumor-reactive, mutation-specific CD8+ T cells could be used as biomarkers of an anti-tumor response. However, such neoantigen-specific T cells are difficult to reliably identify due to their low frequency in peripheral blood and wide range of potential epitope specificities.</AbstractText><AbstractText Label="METHODS">Peripheral blood mononuclear cells (PBMC) from 14 non-small cell lung cancer (NSCLC) patients were collected pre- and post-treatment with the anti-PD-L1 antibody atezolizumab. Using whole exome sequencing and RNA sequencing we identified tumor neoantigens that are predicted to bind to major histocompatibility complex class I (MHC-I) and utilized mass cytometry, together with cellular 'barcoding', to profile immune cells from patients with objective response to therapy (n = 8) and those with progressive disease (n = 6). In parallel, a highly-multiplexed combinatorial tetramer staining was used to screen antigen-specific CD8+ T cells in peripheral blood for 782 candidate tumor neoantigens and 71 known viral-derived control peptide epitopes across all patient samples.</AbstractText><AbstractText Label="RESULTS">No significant treatment- or response associated phenotypic difference were measured in bulk CD8+ T cells. Multiplexed peptide-MHC multimer staining detected 20 different neoantigen-specific T cell populations, as well as T cells specific for viral control antigens. Not only were neoantigen-specific T cells more frequently detected in responding patients, their phenotypes were also almost entirely distinct. Neoantigen-specific T cells from responder patients typically showed a differentiated effector phenotype, most like Cytomegalovirus (CMV) and some types of Epstein-Barr virus (EBV)-specific CD8+ T cells. In contrast, more memory-like phenotypic profiles were observed for neoantigen-specific CD8+ T cells from patients with progressive disease.</AbstractText><AbstractText Label="CONCLUSION">This study demonstrates that neoantigen-specific T cells can be detected in peripheral blood in non-small cell lung cancer (NSCLC) patients during anti-PD-L1 therapy. Patients with an objective response had an enrichment of neoantigen-reactive T cells and these cells showed a phenotype that differed from patients without a response. These findings suggest the ex vivo identification, characterization, and longitudinal follow-up of rare tumor-specific differentiated effector neoantigen-specific T cells may be useful in predicting response to checkpoint blockade.</AbstractText><AbstractText Label="TRIAL REGISTRATION">POPLAR trial NCT01903993 .</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Fehlings</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jhunjhunwala</LastName><ForeName>Suchit</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kowanetz</LastName><ForeName>Marcin</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>O'Gorman</LastName><ForeName>William E</ForeName><Initials>WE</Initials><AffiliationInfo><Affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hegde</LastName><ForeName>Priti S</ForeName><Initials>PS</Initials><AffiliationInfo><Affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sumatoh</LastName><ForeName>Hermi</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Boon Heng</ForeName><Initials>BH</Initials><AffiliationInfo><Affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nardin</LastName><ForeName>Alessandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Becht</LastName><ForeName>Etienne</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Flynn</LastName><ForeName>Susan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ballinger</LastName><ForeName>Marcus</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Newell</LastName><ForeName>Evan W</ForeName><Initials>EW</Initials><AffiliationInfo><Affiliation>immunoSCAPE Pte Ltd, Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yadav</LastName><ForeName>Mahesh</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. yadav.mahesh@gene.com.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>ClinicalTrials.gov</DataBankName><AccessionNumberList><AccessionNumber>NCT01903993</AccessionNumber></AccessionNumberList></DataBank></DataBankList><PublicationTypeList><PublicationType UI="D017427">Clinical Trial, Phase II</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016449">Randomized Controlled Trial</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>09</Month><Day>12</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Immunother Cancer</MedlineTA><NlmUniqueID>101620585</NlmUniqueID><ISSNLinking>2051-1426</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D061067">Antibodies, Monoclonal, Humanized</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000951">Antigens, Neoplasm</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000074322">Antineoplastic Agents, Immunological</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D060890">B7-H1 Antigen</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C423236">CD274 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>52CMI0WC3Y</RegistryNumber><NameOfSubstance UI="C000594389">atezolizumab</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D061067" MajorTopicYN="N">Antibodies, Monoclonal, Humanized</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000951" MajorTopicYN="N">Antigens, Neoplasm</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000302" MajorTopicYN="N">isolation & purification</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000074322" MajorTopicYN="N">Antineoplastic Agents, Immunological</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D060890" MajorTopicYN="N">B7-H1 Antigen</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018414" MajorTopicYN="N">CD8-Positive T-Lymphocytes</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002289" MajorTopicYN="N">Carcinoma, Non-Small-Cell Lung</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016903" MajorTopicYN="N">Drug Monitoring</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008175" MajorTopicYN="N">Lung Neoplasms</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000081246" MajorTopicYN="N">RNA-Seq</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000073359" MajorTopicYN="N">Whole Exome Sequencing</DescriptorName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Atezolizumab</Keyword><Keyword MajorTopicYN="Y">Immunotherapy</Keyword><Keyword MajorTopicYN="Y">NSCLC</Keyword><Keyword MajorTopicYN="Y">Tumor neoantigen-specific T cells</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>04</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>07</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>9</Month><Day>13</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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sortKey="Becht, Etienne" sort="Becht, Etienne" uniqKey="Becht E" first="Etienne" last="Becht">Etienne Becht</name><name sortKey="Lee, Boon Heng" sort="Lee, Boon Heng" uniqKey="Lee B" first="Boon Heng" last="Lee">Boon Heng Lee</name><name sortKey="Nardin, Alessandra" sort="Nardin, Alessandra" uniqKey="Nardin A" first="Alessandra" last="Nardin">Alessandra Nardin</name><name sortKey="Newell, Evan W" sort="Newell, Evan W" uniqKey="Newell E" first="Evan W" last="Newell">Evan W. Newell</name><name sortKey="Sumatoh, Hermi" sort="Sumatoh, Hermi" uniqKey="Sumatoh H" first="Hermi" last="Sumatoh">Hermi Sumatoh</name></country><country name="États-Unis"><noRegion><name sortKey="Jhunjhunwala, Suchit" sort="Jhunjhunwala, Suchit" uniqKey="Jhunjhunwala S" first="Suchit" last="Jhunjhunwala">Suchit Jhunjhunwala</name></noRegion><name sortKey="Flynn, Susan" sort="Flynn, Susan" uniqKey="Flynn S" first="Susan" last="Flynn">Susan Flynn</name><name sortKey="Hegde, Priti S" sort="Hegde, Priti S" uniqKey="Hegde P" first="Priti S" last="Hegde">Priti S. Hegde</name><name sortKey="Kowanetz, Marcin" sort="Kowanetz, Marcin" uniqKey="Kowanetz M" first="Marcin" last="Kowanetz">Marcin Kowanetz</name><name sortKey="O Gorman, William E" sort="O Gorman, William E" uniqKey="O Gorman W" first="William E" last="O'Gorman">William E. O'Gorman</name><name sortKey="Yadav, Mahesh" sort="Yadav, Mahesh" uniqKey="Yadav M" first="Mahesh" last="Yadav">Mahesh Yadav</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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|wiki= Bois
|area= PoplarV1
|flux= Main
|étape= Exploration
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|clé= pubmed:31511069
|texte= Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment.
}}
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