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+ Tregs and myeloid-derived suppressor cells, tumor antigen-specific regulatory T cells interfere with the detection of anti-tumor immunity following 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 following 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, antigen-specific CD8+ regulatory T cells 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 following 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 antigen-specific regulatory T cells arise spontaneously in some prostate cancer patients, persist during immunization, and can prevent the detection of antigen-specific effector responses by an IL-35-dependent mechanism.

CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer

“…As suggested by Ness and colleagues (11), one of the potential explanations is that CD8 þ T cells might display immunosuppressive functions in the prostate. Several studies have indeed described the presence of immunosuppressive CD8 þ T cells in tumors, including in prostate tumors (36)(37)(38).…”

Dynamicity of Immune Regulation during Visceral Leishmaniasis

“…IL-35 association has been shown with atherosclerosis (Lin et al, 2012), hepatitis B (Liu et al, 2011);leukemia (Wu et al, 2012), and tumor (Olson et al, 2012;Wang et al, 2013), but its regulatory role in infectious diseases is yet to be established. Association of IL-35 with the progression of VL may lead to new targets for better intervention and control of the disease.…”

Immune regulation at the fetal‐maternal interface with focus on decidual macrophages

“…may be due to methodological issues, possibly kinetic-related, rather than lack of expression by these cells. IL-35 has been shown to contribute to suppressive function and to protect against several autoimmune and inflammatory disorders and to alleviate graft-versus-host disease in allogeneic stem cell transplantation (Collison et al, 2007;Niedbala et al, 2007;Collison et al, 2010;Olson et al, 2012;Shen et al, 2014;Liu et al, 2015), making it an interesting candidate for promoting fetal tolerance. The production of IL-35 by decidual macrophages is however intriguing, since IL-35 has been shown to be mainly restricted to Treg cells in mice (Collison et al, 2007) and, in addition, the production by human Treg cells has been debated (Allan et al, 2008;Bardel et al, 2008).…”