Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity

J Exp Med. 2010 Sep 27;207(10):2187-94. doi: 10.1084/jem.20100643. Epub 2010 Sep 6.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / immunology*
  • Antigens, Surface / metabolism
  • Apoptosis Regulatory Proteins / immunology*
  • Apoptosis Regulatory Proteins / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Hepatitis A Virus Cellular Receptor 2
  • Immune Tolerance / immunology
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Lymphocyte Activation*
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice
  • Molecular Targeted Therapy
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus / immunology*
  • Receptors, Virus / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Interleukin-2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma