CD8+ T cell-independent mechanisms of PD-1-mediated suppression of anti-tumor immunity in mice

Over expression of the inhibitory receptor PD-1 commonly occurs in cancer, and PD-1 signaling suppresses protective anti-tumor immune responses. While early clinical trials with PD-1 inhibitors in cancer have been promising, the majority of patients have not shown durable clinical benefit, and the mechanisms underlying both successes and failures remain poorly defined. CD8 + T cells can directly kill tumor cells, and CD8 + T cell infiltration of human tumors positively correlates with responses to PD-1 blockade. CD8 + T cells in tumors (TILs) often show high expression of PD-1; however, PD-1 is also expressed by other cell types, including CD4 + T cells, regulatory T cells (Treg), B cells, and some myeloid cells. Consequently, we hypothesized that loss of PD-1 only on CD8 + T cells may not be sufficient to control tumor burden. To address this question, we compared tumor responses in mice completely deficient for PD-1 (referred to as cKO) or selectively deficient for PD-1 on CD8 + T cells (E8i-cre PD-1 f/f mice, referred to as CD8ΔPD-1). Following subcutaneous implantation of MC38 adenocarcinoma tumor cells, 100% of PD-1 cKO mice cleared the tumor. In contrast, only 70% of CD8ΔPD-1 mice controlled the tumor. Moreover, in CD8ΔPD-1 mice that controlled tumor, the average time to clearance was delayed compared to PD-1 cKO mice. In both PD-1 cKO and CD8ΔPD-1 mice, CD8 + TILs showed elevated granzyme B levels and an increased CD8 to Treg ratio, suggesting that CD8 + T cell-independent mechanisms contribute to immunity following loss of PD-1 in MC38 tumors. On-going work examining both tumor cells and infiltrating immune cells is focused on identifying these CD8 + T cell-independent mechanisms of PD-1-mediated suppression.