title: Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade.
abstract: 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.
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Olson
authors.forename: Ewa
authors.initials: E
authors.lastname: Jankowska-Gan
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Becker
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McNeel
mesh_terms: D000135:Acid Phosphatase; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D002478:Cells, Cultured; D002986:Clinical Trials as Topic / Q000379:methods; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D007378:Interleukins; D019444:Vaccines, DNA; C532417:interleukin-35, human; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases