451 Blockade of tumor cell-intrinsic PD-1 inhibits Merkel cell carcinoma growth

Merkel Cell Carcinoma (MCC) is a rare, but highly aggressive cancer of the skin. In MCC patients, inhibitors targeting the programmed cell death-1 (PD-1) immune checkpoint pathway have yielded remarkable antitumor activity by stimulating cancer-specific T-cell immunity. Here, we identify a previously unknown role for PD-1 as a growth-promoting receptor intrinsic to MCC cells. In four established human MCC cell lines, MKL-1, MKL-2, MS-1, and WaGa, RT-PCR amplification and sequencing revealed expression of the full PD-1 (PDCD1) mRNA coding sequence. Immunoblot and FACS analyses demonstrated PD-1 protein expression. Immunofluorescence staining also revealed PD-1 expression by CK20+CD45- MCC cells in clinical tumor biospecimens. Binding of MCC-PD-1 by its ligands, PD-L1 or PD-L2, induced protumorigenic mTOR signaling and mitochondrial reactive oxygen species (mROS) generation, both of which were inhibited by the clinically approved PD-1 blocking antibody, nivolumab. Consistently, PD-1 blockade suppressed MCC in vitro proliferation and in vivo tumor xenograft growth in mice lacking adaptive immunity. Our results identify MCC-intrinsic PD-1 signaling as a novel tumor growth-accelerating mechanism and therapeutic target, the blockade of which might contribute to PD-1 checkpoint inhibitor efficacy in MCC patients.