Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo

Tumor-specific CD8 T-cell peripheral tolerance occurs through clonal deletion, suppression, and the induction of anergy and can limit the generation of anti-tumor immunity. Several groups have demonstrated that prostate cancer can render tumor-specific CD8 T cells anergic, suggesting reversing tumor-induced anergy may greatly augment antitumor immunity. Recent work has demonstrated that signaling through the OX40 (CD134) co-stimulatory receptor, a member of the TNFR super-family, can augment CD4 and CD8 T-cell expansion, differentiation, and the generation of memory cells. However, whether OX40 ligation can reverse CD8 T-cell anergy, and more specifically, tumor-induced CD8 T-cell anergy, remains unclear. In the current study, we demonstrate that OX40 ligation can reverse CD8 T-cell anergy to a prostate-specific self-Ag in non-tumor-bearing hosts. Furthermore, OX40 engagement reversed tumor-specific CD8 T-cell anergy and restored the proliferative capacity of tumor-reactive CD8 T cells, which attenuated tumor growth and enhanced the survival of tumor-bearing hosts. These data demonstrate that OX40 ligation can rescue the function of anergic self- or tumor-reactive CD8 T cells in vivo and suggests that OX40-mediated therapy may provide a novel means of boosting anti-tumor immunity by restoring the responsiveness of previously anergic tumor-specific CD8 T cells.