Circulating cancer-specific CD8 T cell frequency is associated with response to PD-1 blockade in Merkel cell carcinoma

Abstract

Understanding cancer immunobiology has been hampered by difficulty identifying cancer-specific Tcells. Merkel cell polyomavirus (MCPyV) causes most Merkel cell carcinomas (MCCs). All patients with virus-driven MCC express MCPyV oncoproteins, facilitating identification of virus (cancer)-specific Tcells. We studied MCPyV-specific Tcells from 27 patients with MCC using MCPyV peptide-HLA-I multimers, 26-color flow cytometry, single-cell transcriptomics, and Tcell receptor (TCR) sequencing. In a prospective clinical trial, higher circulating MCPyV-specific CD8 Tcell frequency before anti-PD-1 treatment was strongly associated with 2-year recurrence-free survival (75% if detectable, 0% if undetectable, p= 0.0018; ClinicalTrial.gov: NCT02488759). Intratumorally, such Tcells were typically present, but their frequency did not significantly associate with response. Circulating MCPyV-specific CD8 Tcells had increased stem/memory and decreased exhaustion signatures relative to their intratumoral counterparts. These results suggest that cancer-specific CD8 Tcells in the blood may play a role in anti-PD-1 responses. Thus, strategies that augment their number or mobilize them into tumors could improve outcomes.