In the present study, we describe forkhead box O3 (FOXO3)-specific, cytotoxic CD8+ T cells existent among peripheral-blood mononuclear cells (PBMCs) of cancer patients. FOXO3 immunogenicity appears specific, as we did not detect reactivity toward FOXO3 among T cells in healthy individuals. FOXO3 may naturally serve as a target antigen for tumor-reactive T cells as it is frequently over-expressed in cancer cells. In addition, expression of FOXO3 plays a critical role in immunosuppression mediated by tumor-associated dendritic cells (TADCs). Indeed, FOXO3-specific cytotoxic T lymphocytes (CTLs) were able to specifically recognize and kill both FOXO3-expressing cancer cells as well as dendritic cells. Thus, FOXO3 was processed and presented by HLA-A2 on the cell surface of both immune cells and cancer cells. As FOXO3 programs TADCs to become tolerogenic, FOXO3 signaling thereby comprises a significant immunosuppressive mechanism, such that FOXO3 targeting by means of specific T cells is an attractive clinical therapy to boost anticancer immunity. In addition, the natural occurrence of FOXO3-specific CTLs in the periphery suggests that these T cells hold a function in the complex network of immune regulation in cancer patients.
Keywords: APC, antigen presenting cell; CTL; CTL, cytotoxic T lymphocyte; CTLA4, cytotoxic T-lymphocyte associated protein 4; DC, dendritic cell; FOXO3; FOXO3, forkhead box O3; IDO, indoleamine-2,3-dioxygenase; PBMC, peripheral blood mononuclear cell; TADC, tumor-associated DCs; TGFβ, tumor growth factor β; TNFα, tumor necrosis factor α; Tregs, regulatory T cell; antigens; immune regulation; tumor-associated dendritic cells.