Interleukin-35 Limits Anti-Tumor Immunity

Immunity. 2016 Feb 16;44(2):316-29. doi: 10.1016/j.immuni.2016.01.013. Epub 2016 Feb 9.

Abstract

Regulatory T (Treg) cells pose a major barrier to effective anti-tumor immunity. Although Treg cell depletion enhances tumor rejection, the ensuing autoimmune sequelae limits its utility in the clinic and highlights the need for limiting Treg cell activity within the tumor microenvironment. Interleukin-35 (IL-35) is a Treg cell-secreted cytokine that inhibits T cell proliferation and function. Using an IL-35 reporter mouse, we observed substantial enrichment of IL-35(+) Treg cells in tumors. Neutralization with an IL-35-specific antibody or Treg cell-restricted deletion of IL-35 production limited tumor growth in multiple murine models of human cancer. Limiting intratumoral IL-35 enhanced T cell proliferation, effector function, antigen-specific responses, and long-term T cell memory. Treg cell-derived IL-35 promoted the expression of multiple inhibitory receptors (PD1, TIM3, LAG3), thereby facilitating intratumoral T cell exhaustion. These findings reveal previously unappreciated roles for IL-35 in limiting anti-tumor immunity and contributing to T cell dysfunction in the tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Blocking / administration & dosage*
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Immunologic Memory
  • Interleukins / genetics
  • Interleukins / immunology
  • Interleukins / metabolism*
  • Melanoma, Experimental / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism
  • Skin Neoplasms / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Tumor Microenvironment

Substances

  • Antibodies, Blocking
  • Antigens, CD
  • CD223 antigen
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Interleukins
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus
  • interleukin-35, mouse