PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus, and overall survival

EJ Lipson, JG Vincent, M Loyo, LT Kagohara… - Cancer immunology …, 2013 - AACR
EJ Lipson, JG Vincent, M Loyo, LT Kagohara, BS Luber, H Wang, H Xu, SK Nayar, TS Wang…
Cancer immunology research, 2013AACR
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 …
Abstract
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(+) 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(-) MCCs were independently associated with worse overall survival [HR 3.12; 95% confidence interval, 1.28–7.61; P = 0.012]. These findings suggest that an endogenous immune response promotes PD-L1 expression in the MCC microenvironment when MCPyV is present, and provide a rationale for investigating therapies blocking PD-1/PD-L1 for patients with MCC. Cancer Immunol Res; 1(1); 54–63. ©2013 AACR.
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