Abstract
Despite successes, thus far, a significant proportion of the patients treated with anti-PD1 antibodies have failed to respond. We use mouse tumor models of anti-PD1 sensitivity and resistance and flow cytometry to assess tumor-infiltrating immune cells immediately after therapy. We demonstrate that the expression levels of T-cell PD1 (PD1(lo)), myeloid, and T-cell PDL1 (PDL1(hi)) in the tumor microenvironment inversely correlate and dictate the efficacy of anti-PD1 mAb and function of intratumor CD8(+) T cells. In sensitive tumors, we reveal a threshold for PD1 downregulation on tumor-infiltrating CD8(+) T cells below which the release of adaptive immune resistance is achieved. In contrast, PD1(hi) T cells in resistant tumors fail to be rescued by anti-PD1 therapy and remain dysfunctional unless intratumor PDL1(lo) immune cells are targeted. Intratumor Tregs are partly responsible for the development of anti-PD1-resistant tumors and PD1(hi) CD8(+) T cells. Our analyses provide a framework to interrogate intratumor CD8(+) T-cell PD1 and immune PDL1 levels and response in human cancer.
©2015 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity
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Adenocarcinoma / immunology
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Adenocarcinoma / therapy*
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Animals
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Antibodies, Monoclonal / therapeutic use*
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B7-H1 Antigen / physiology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism*
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Colonic Neoplasms / immunology
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Colonic Neoplasms / therapy*
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Down-Regulation
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Female
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Gene Expression Regulation, Neoplastic / immunology*
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Immunization, Passive*
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / metabolism*
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Mammary Neoplasms, Experimental / immunology
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Mammary Neoplasms, Experimental / therapy*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Programmed Cell Death 1 Receptor / biosynthesis
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / physiology*
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T-Lymphocytes, Regulatory / immunology
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Tumor Microenvironment / immunology
Substances
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Antibodies, Monoclonal
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B7-H1 Antigen
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Cd274 protein, mouse
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Neoplasm Proteins
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor