Abstract
The immune response plays an important role in staving off cancer; however, mechanisms of immunosuppression hinder productive anti-tumor immunity. T cell dysfunction or exhaustion in tumor-bearing hosts is one such mechanism. PD-1 has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1-PD-1L interactions has been shown to partially restore T cell function. We have found that T cell immunoglobulin mucin (Tim) 3 is expressed on CD8(+) tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors. All Tim-3(+) TILs coexpress PD-1, and Tim-3(+)PD-1(+) TILs represent the predominant fraction of T cells infiltrating tumors. Tim-3(+)PD-1(+) TILs exhibit the most severe exhausted phenotype as defined by failure to proliferate and produce IL-2, TNF, and IFN-γ. We further find that combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Surface / immunology*
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Antigens, Surface / metabolism
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Apoptosis Regulatory Proteins / immunology*
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Apoptosis Regulatory Proteins / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Hepatitis A Virus Cellular Receptor 2
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Immune Tolerance / immunology
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Interferon-gamma / biosynthesis
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Interferon-gamma / immunology
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Interleukin-2 / immunology
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Interleukin-2 / metabolism
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Lymphocyte Activation*
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Lymphocytes, Tumor-Infiltrating / immunology*
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Lymphocytes, Tumor-Infiltrating / pathology
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Mice
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Molecular Targeted Therapy
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Neoplasms, Experimental / immunology*
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Neoplasms, Experimental / pathology
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Programmed Cell Death 1 Receptor
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Receptors, Virus / immunology*
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Receptors, Virus / metabolism
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Signal Transduction
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology
Substances
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Antigens, Surface
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Apoptosis Regulatory Proteins
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Havcr2 protein, mouse
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Hepatitis A Virus Cellular Receptor 2
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Interleukin-2
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Receptors, Virus
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Tumor Necrosis Factor-alpha
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Interferon-gamma