Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma.

Abstract

Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes. IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm²) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs. No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3⁺ (P = 0.004) and CD8⁺ (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8⁺ T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3⁺ (P = 0.026) and CD8⁺ (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV⁺ but not MCPyV^- MCC. TCRseq revealed clonal overlap among MCPyV⁺ samples, suggesting an antigen-specific response against a unifying antigen. These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. Clin Cancer Res; 22(22); 5553-63. ©2016 AACR.