Ascites tumor cell-expressed PD-1 promotes ovarian cancer progression via the MAPK/ERK pathway

Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule mainly expressed on T cells that mediates tumor immune escape. However, the potential function of PD-1 on tumor cells remains largely unknown. Here, we showed that PD-1 was expressed on ascitic ovarian cancer cells of both mouse and a portion of clinical samples. Ovarian cancer-PD-1 promoted proliferation, migration, and tumorigenesis, which were independent of adaptive immunity. In contrast, PD-1 inhibition with knockout or antibody blockade reversed the tumor-promoting effects. Mechanistically, ovarian cancer-PD-1 binding to ascitic soluble sPD-L1, while antibody-mediated PD-1/PD-L1 blockade inhibited protumorigenic MAPK/ERK signaling, thus enhancing phosphorylation of ERK1/2 and further promoting related gene expression. Moreover, pharmacologic inhibition of p-ERK1/2 reversed ovarian cancer-PD-1: sPD-L1-dependent tumor progression and prolonged survival in mouse ovarian cancer. Our results identify an ovarian cancer-PD-1-sPD-L1-p-ERK1/2 axis as a tumor accelerator mechanism; thus, p-ERK1/2 inhibitors may optimize the anti-tumor efficacy in ovarian cancer patients via targeting ascitic cancer cell-PD-1.