PD-L 1 Expression in the Merkel Cell Carcinoma Microenvironment : Association with In fl ammation , Merkel Cell Polyomavirus , and Overall Survival

Merkel cell carcinoma (MCC) is a lethal, virus-associated cancer that lacks effective therapies for advanced disease. Agents blocking the PD-1/PD-L1 pathway have shown objective, durable tumor regressions in patients with advanced solid malignancies and efficacy has been linked to PD-L1 expression in the tumor microenvironment. To investigate whether MCC might be a target for PD-1/PD-L1 blockade, we examined MCC PD-L1 expression, its association with tumor-infiltrating lymphocytes (TIL), Merkel cell polyomavirus (MCPyV), and overall survival. Sixty-seven MCC specimens from 49 patients were assessed with immunohistochemistry for PD-L1 expression by tumor cells and TILs, and immune infiltrates were characterized phenotypically. Tumor cell and TIL PD-L1 expression were observed in 49% and 55% of patients, respectively. In specimens with PD-L1 (þ) tumor cells, 97% (28/29) showed a geographic association with immune infiltrates. Among specimens with moderate-severe TIL intensities, 100% (29/29) showed PD-L1 expression by tumor cells. Significant associations were also observed between the presence of MCPyV DNA, a brisk inflammatory response, and tumor cell PD-L1 expression: MCPyV(-) tumor cells were uniformly PD-L1(-). Taken together, these findings suggest that a local tumor-specific and potentially MCPyV-specific immune response drives tumor PD-L1 expression, similar to previous observations in melanoma and head and neck squamous cell carcinomas. In multivariate analyses, PD-L1(-)MCCswere independently associatedwithworse overall survival [HR 3.12; 95% confidence interval, 1.28– 7.61; P 1⁄4 0.012]. These findings suggest that an endogenous immune response promotes PD-L1 expression in theMCCmicroenvironment whenMCPyV is present, and provide a rationale for investigating therapies blocking PD-1/PD-L1 for patients with MCC. Cancer Immunol Res; 1(2); 1–10. 2013 AACR.