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

Understanding immunotherapy response and resistance is challenging due to difficulty identifying cancer-specific CD8 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 from a neoadjuvant anti-PD-1 trial. Higher MCPyV-specific CD8 T-cell frequency in pre-treatment blood (but not tumors) correlated with response (p=0.0056). Single cell RNAseq revealed MCPyV-specific CD8 T cells in blood with increased stem/memory signatures and decreased exhaustion signatures relative to their intratumoral counterparts. Number of circulating cancer-specific T cells is likely most linked to primary response to immunotherapy as longitudinal samples documented emergence of additional resistance mechanisms, amidst abundant circulating cancer-specific CD8 T cells. These results suggest that blood acts as an important reservoir of cancer-specific CD8 T cells and suggests adoptive cell therapies may be particularly effective in patients without such cells. Overall design: We used 10x Genomic's Chromium Single Cell 5' Reagent Kits (v2 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 a performed on T cells expaned from patient tumors using HLA-I matched DNA barcoded MHC-I multimers.