Relevance of host and tumor PD-L1 expression in PD-L1 and PD-1 blockade

Abstract

Abstract Therapeutic blockade of PD-1 or PD-L1 with monoclonal antibodies (mAb) leads to durable tumor regressions in patients across cancer types. Clinical responses to PD-L1 and PD-1 blockade may be associated with increased PD-L1 expression in the tumor tissues, tumor-infiltrating T cells, and tumor neoantigens. However, it is unclear which patient population(s) benefits from these treatments. Furthermore, why do some patients with PD-L1 negative tumor respond to PD-L1 and PD-1 blockade therapy? To dissect the molecular and cellular mechanisms that account for the clinical efficacy of PD-L1 and PD-1 blockade, we used Rag1tm1Mom(Rag1−/−), NOD.SCID gc-deficient (NSG), PD-L1 genetic deficient (PD-L1−/−), and PD-1 genetic deficient (PD-1−/−) mice, and studied PD-L1 blockade in MC38, ID8, B16-F10, and LLC models. We found a loss of therapeutic effect of anti-PD-L1 mAb treatment in Rag1−/−, NSG, PD-L1−/−, and PD-1−/−mice. We demonstrated the importance of PD-L1 expression on antigen presenting cells (APCs), particularly dendritic cells (DCs) in the tumor microenvironment and draining lymph nodes, in anti-PD-L1 treatment efficacy. Thus, the host immune system is indispensable for anti-PD-L1 therapy, and the host, rather than cancer cell-intrinsic PD-L1 may account for the therapeutic efficacy of PD-L1 signaling blockade.