Merkel cell polyomavirus-specific and CD39+CLA+ CD8 T cells as blood-based predictive biomarkers for PD-1 blockade in Merkel cell carcinoma

Abstract

Merkel cell carcinoma is a skin cancer often driven by Merkel cell polyomavirus (MCPyV) with high rates of response to anti-PD-1 therapy despite low mutational burden. MCPyV-specific CD8 T cells are implicated in anti-PD-1-associated immune responses and provide a means to directly study tumor-specific T cell responses to treatment. Using mass cytometry and combinatorial tetramer staining, we find that baseline frequencies of blood MCPyV-specific cells correlated with response and survival. Frequencies of these cells decrease markedly during response to therapy. Phenotypes of MCPyV-specific CD8 T cells have distinct expression patterns of CD39, cutaneous lymphocyte-associated antigen (CLA), and CD103. Correspondingly, overall bulk CD39⁺CLA⁺ CD8 T cell frequencies in blood correlate with MCPyV-specific cell frequencies and similarly predicted favorable clinical outcomes. Conversely, frequencies of CD39⁺CD103⁺ CD8 T cells are associated with tumor burden and worse outcomes. These cell subsets can be useful as biomarkers and to isolate blood-derived tumor-specific T cells.

Keywords: CD8 T cells; CyTOF; MCPyV; Merkel cell carcinoma; Merkel cell polyomavirus; TCR sequencing; antigen-specific T cells; checkpoint blockade; high-dimensional analysis; immunotherapy; tumor-specific T cells.