Cancer-specific CD8 T cell frequency at baseline in blood correlates with response to PD-1 blockade in Merkel cell carcinoma.

Understanding immunotherapy resistance is challenging due to difficulty identifying cancer-specific T cells. Merkel cell carcinoma (MCC) is typically driven by Merkel cell polyomavirus (MCPyV), facilitating identification of cancer-specific T cells across patients. We characterized cancer-specific T cells in 35 MCC patients, including participants in a neoadjuvant anti-PD-1 trial. Higher MCPyV-specific CD8 T-cell frequency in pre-treatment blood (but not tumors) correlated with response (p=0.005). Single-cell transcriptomics revealed MCPyV-specific CD8 T cells in blood had increased stem/memory signatures and decreased exhaustion signatures relative to their intratumoral counterparts. While frequency of peripheral cancer-specific T cells was associated with response to initial PD-(L)1 blockade, longitudinal study of acquired resistance revealed immune evasion by tumor-cell MHC-I downregulation despite cancer-specific T cell expansion to 0.5% in blood. Blood thus appears to be an important reservoir of cancer-specific CD8 T cells and adoptive cell therapies may be particularly effective in patients without such cells. We used 10x Genomic's Chromium Single Cell 5' Reagent Kits (v1.1 Chemistry Dual Index) with Feature Barcoding technology for Cell Surface Protein and Immune Receptor to identify antigen specific T cell V(D)J sequences. This was performed on tumor and blood specimen taken from 7 pateints. Due to patient privacy concerns, only processed and not raw sequencing reads were deposited. ***raw data were not included due to patient privacy regulations***