Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade

J Immunol. 2012 Dec 15;189(12):5590-601. doi: 10.4049/jimmunol.1201744. Epub 2012 Nov 14.


Regulatory T cells play important roles in cancer development and progression by limiting the generation of innate and adaptive anti-tumor immunity. We hypothesized that in addition to natural CD4(+)CD25(+) regulatory T cells (Tregs) and myeloid-derived suppressor cells, tumor Ag-specific Tregs interfere with the detection of anti-tumor immunity after immunotherapy. Using samples from prostate cancer patients immunized with a DNA vaccine encoding prostatic acid phosphatase (PAP) and a trans-vivo delayed-type hypersensitivity (tvDTH) assay, we found that the detection of PAP-specific effector responses after immunization was prevented by the activity of PAP-specific regulatory cells. These regulatory cells were CD8(+)CTLA-4(+), and their suppression was relieved by blockade of CTLA-4, but not IL-10 or TGF-β. Moreover, Ag-specific CD8(+) Tregs were detected prior to immunization in the absence of PAP-specific effector responses. These PAP-specific CD8(+)CTLA-4(+) suppressor T cells expressed IL-35, which was decreased after blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35 reversed PAP-specific suppression of tvDTH response. PAP-specific CD8(+)CTLA-4(+) T cells also suppressed T cell proliferation in an IL-35-dependent, contact-independent fashion. Taken together, these findings suggest a novel population of CD8(+)CTLA-4(+) IL-35-secreting tumor Ag-specific Tregs arise spontaneously in some prostate cancer patients, persist during immunization, and can prevent the detection of Ag-specific effector responses by an IL-35-dependent mechanism.

Publication types

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

MeSH terms

  • Acid Phosphatase
  • Animals
  • CD8-Positive T-Lymphocytes / enzymology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • CTLA-4 Antigen / antagonists & inhibitors*
  • CTLA-4 Antigen / biosynthesis
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / immunology
  • Cells, Cultured
  • Clinical Trials as Topic / methods
  • Coculture Techniques
  • Epitopes, T-Lymphocyte / immunology*
  • Growth Inhibitors / antagonists & inhibitors*
  • Growth Inhibitors / biosynthesis
  • Humans
  • Interleukins / antagonists & inhibitors*
  • Interleukins / biosynthesis
  • Interleukins / metabolism
  • Male
  • Mice
  • Mice, SCID
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / immunology*
  • Prostatic Neoplasms / prevention & control
  • Protein Tyrosine Phosphatases / physiology*
  • T-Lymphocytes, Regulatory / enzymology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Tumor Escape / immunology
  • Vaccines, DNA / administration & dosage
  • Vaccines, DNA / immunology


  • CTLA-4 Antigen
  • Cancer Vaccines
  • Epitopes, T-Lymphocyte
  • Growth Inhibitors
  • Interleukins
  • Vaccines, DNA
  • interleukin-35, human
  • Acid Phosphatase
  • prostatic acid phosphatase
  • Protein Tyrosine Phosphatases