Relevance of host and tumor PD-L1 in PD-L1 pathway blockade

Abstract PD-L1 and PD-1 pathway blockade is a promising therapy against cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Using three tumor bearing mouse models that differ in their sensitivity to PD-L1 blockade, MC38, ID8, and B16-F10, we found a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1 and PD-1 deficient mice. In contrast, knockout or overexpression of PD-L1 in tumor cells had no effect on PD-L1 blockade. Human and murine studies show high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Further, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlates with the efficacy of anti-PD-1 and anti-PD-1 plus anti-CTLA-4 therapy. Thus, PD-L1+ dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.