CD8+ Foxp3+ Regulatory T Cells Mediate Immunosuppression in Prostate Cancer

Abstract

Prostate cancer is the most common cancer among men in the United States and the second most common malignant cause of male deaths in the United States. There is currently no effective therapy for late-stage disease, whereas surgery or radiation therapy is the only choice for early-stage disease. Immunotherapy affords a promising approach to the treatment of various types of cancer, including prostate cancer (1 -5). Although peptide-or dendritic cell -based vaccines can induce antigenspecific immune responses, objective clinical responses remain infrequent and transient (3,6). A possible explanation is that tumor cells may create an immunosuppressive environment in cancer patients. Thus, a better understanding of the interaction between tumor-infiltrating immune cells and cancer cells is critical to efforts to devise strategies that would enhance the therapeutic efficacy of immunologic interventions.Recent studies indicate that preexisting CD4 + regulatory T (Treg) cells at tumor sites may pose major obstacles to effective cancer immunotherapy, as these cells have a potent ability to suppress host immune responses (7 -9). Indeed, increased proportions of CD4 + CD25 + Treg cells in the total CD4 + T-cell populations have been documented in patients with different types of cancers, including lung, breast, and ovarian tumors (10 -12). Our recent findings further show the presence of antigen-specific CD4 + Treg cells at tumor sites, where they induce antigen-specific and local immune tolerance (7,8). The removal or elimination of Treg cell populations with anti-CD25 monoclonal antibody (mAb) treatment results in effective rejection of transplanted tumors in animal models (13), further suggesting a functional role for these Treg cells in tumor progression and immunosuppression.Because Treg cell -mediated immunosuppression exists at tumor sites, a new strategy for depletion of Treg cells or reversal of the suppressive function of Treg cells will be important in efforts to induce antigen-specific effector T cells. Thus, we recently showed that Toll-like receptor 8 (TLR8) ligands can specifically reverse the suppressive function of both antigen-specific and

Rapid tolerization of virus-activated tumor-specific CD8 + T cells in prostate tumors of TRAMP mice

“…In our TRP-SIY model, effector CTLs rapidly become tolerant in antigen-expressing prostate tumors without being physically deleted. Kiniwa et al recently demonstrated the importance of CD8 ϩ Foxp3 ϩ suppressor cells in human prostate tumors (35). However, both intracellular staining and transcriptional profiling show that tolerized 2C cells in the TRP-SIY mice are not converted into Foxp3 ϩ suppressor cells (data not shown).…”

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

“…Siegmund et al describe this phenotype to be uniquely present in human tonsil tissue, 41 however their presence was also demonstrated in human prostate cancer. 42 Whether these T cells with tolerogenic phenotype are a reflection of suppressed local immunity or part of an ongoing adaptive immune response can not be concluded from this data.…”

Determination of Th1/Th2/Th17 Cytokines in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

“…The paper mentions the significance of immunological vigilance and the fact that CD8 Treg may promote tumoral growth. It also describes this cell subpopulation in patients with multiple sclerosis in whom lower numbers of these cells were correlated with relapse, a fact that may evidence their immunosuppressant role in the control of autoimmune diseases (Giovanni Frisullo, 2010;Chaput, 2009;Kiniwa, 2007). Recently described populations of CD8+ Treg include CD8+ IL-10+ cells present in ovarian carcinoma, which are induced by plasmocytoid dendritic cells infiltrating the tumor.…”