Abstract
Accumulation of CD103+CD8+ resident memory T (TRM) cells in human lung tumors has been associated with a favorable prognosis. However, the contribution of TRM to anti-tumor immunity and to the response to immune checkpoint blockade has not been clearly established. Using quantitative multiplex immunofluorescence on cohorts of non-small cell lung cancer patients treated with anti-PD-(L)1, we show that an increased density of CD103+CD8+ lymphocytes in immunotherapy-naive tumors is associated with greatly improved outcomes. The density of CD103+CD8+ cells increases during immunotherapy in most responder, but not in non-responder, patients. CD103+CD8+ cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and CD39. CD103+CD8+ tumor TRM, but not CD103-CD8+ tumor-infiltrating counterparts, express Aiolos, phosphorylated STAT-3, and IL-17; demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells; and frequently display oligoclonal expansion of TCR-β clonotypes. These results explain why CD103+CD8+ TRM are associated with better outcomes in anti-PD-(L)1-treated patients.
Keywords:
Aiolos, AhR, and T-bet transcription factors; CD103 integrin; CD8 TRM cells; CTL; ICB response biomarkers; TCR repertoire; Tc17; anti-PD-1 immunotherapy; lung cancer; tumor-infiltrating lymphocytes.
© 2020 The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / genetics
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Antigens, CD / immunology
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Antineoplastic Agents, Immunological / therapeutic use*
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B7-H1 Antigen / antagonists & inhibitors
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B7-H1 Antigen / genetics
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B7-H1 Antigen / immunology
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CD8 Antigens / genetics
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CD8 Antigens / immunology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / immunology*
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Carcinoma, Non-Small-Cell Lung / mortality
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Cytotoxicity, Immunologic / drug effects
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Gene Expression Regulation
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Humans
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Ikaros Transcription Factor / genetics
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Ikaros Transcription Factor / immunology
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Immunologic Memory
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Immunotherapy / methods
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Integrin alpha Chains / genetics
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Integrin alpha Chains / immunology
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Interleukin-17 / genetics
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Interleukin-17 / immunology
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology*
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Lung Neoplasms / mortality
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Lymphocyte Activation / drug effects
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Lymphocyte Count
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Lymphocytes, Tumor-Infiltrating / drug effects
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Lymphocytes, Tumor-Infiltrating / immunology*
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Lymphocytes, Tumor-Infiltrating / pathology
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Phosphorylation
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Prognosis
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology*
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Retrospective Studies
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / immunology
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Signal Transduction
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Survival Analysis
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / immunology
Substances
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Antigens, CD
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Antineoplastic Agents, Immunological
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B7-H1 Antigen
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CD274 protein, human
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CD8 Antigens
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IKZF3 protein, human
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Integrin alpha Chains
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Interleukin-17
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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STAT3 Transcription Factor
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STAT3 protein, human
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alpha E integrins
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Ikaros Transcription Factor