Background: Naturally occurring regulatory T (Treg) cells play an essential role for immunological unresponsiveness to self-tumor-antigens. Yet, how they stably suppress self-tumor-antigen-specific T cells remains unclear. In particular, it is unknown whether Treg cell-mediated suppression for a limited period has a critical long-lasting effect on cell fate and antigen reactivity of self-tumor-antigen-specific T cells.

Experimental procedures: To demonstrate Treg-cell effect on proliferation, cytokine production, and cell fate of self-tumor-antigen-specific CD8+ T cells, CD8+ T cells from peripheral blood mononuclear cells (PBMCs) of healthy individuals were stimulated with a melanocyte differentiation antigen Melan-A/ MART-1, expressed by normal melanocytes and some melanoma cells, with/without FoxP3+CD25+CD4+ Treg cells. Melan-A/ MART-1-specific CD8+ T-cell induction and their phenotypes were investigated.

Results: Melan-A/ MART-1-specific CD8+ T-cell induction was reduced by the presence of Treg cells. Self-tumor-antigen-specific CD8+ T cells co-cultured with Treg cells underwent one cell division and stopped further proliferation due to the lack of co-stimulation from antigen-presenting cells through Treg-cell suppression. They harbored low-affinity T-cell receptors and an anergic phenotype (i.e., hypo-proliferative and cytokine hypo-producing upon antigen re-stimulation) defined by expression of CCR7 and co-inhibitory molecules such as CTLA-4. Melan-A/ MART-1-specific CD8+ T cells with this anergic phenotype were detected ex vivo in the periphery and contributed to the tolerance of self-tumor-antigens.

Conclusions: Treg-cell-mediated induction of anergy in self- antigen tumor-specific CD8+ T cells inhibits their activation in cancer patients after immunotherapy, and neo-antigens associated with tumor-specific gene mutations may become a main target of CD8+ T cells inducing actual tumor regression.

Citation Format: Yuka Maeda, Hiroyoshi Nishikawa, Shimon Sakaguchi. Self-tumor-antigen-specific CD8 T cells were suppressed by regulatory T cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B035.