Journal
JOURNAL OF IMMUNOLOGY
Volume 189, Issue 12, Pages 5590-5601Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1201744
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Funding
- National Institutes of Health [R01 CA14260, R01-AI066219-05, R01 AI091977]
- U.S. Army Medical Research and Materiel Command Prostate Cancer Research Program [W81XWH-05-1-0404, W81XWH-11-1-0196]
- University of Wisconsin Carbone Cancer Center
- European Union
- National Cancer Institute Comprehensive Cancer Center [CA21765]
- American Lebanese Syrian Associated Charities
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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-beta. 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. The Journal of Immunology, 2012, 189: 5590-5601.
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