Circulating Neoantigen- and Viral Oncoprotein–Specific CD8+ T Cells Share a Transcriptional Signature

Abstract Tumor-specific CD8+ T cells in blood seem to be important for and predictive of response to anti–PD-1 therapies. However, as most tumor antigens are unique to a given patient, the identification of tumor-specific CD8+ T cells is not routinely feasible. In this study, we characterized polyomavirus-specific CD8+ T cells from the blood of 17 patients with virus-driven Merkel cell carcinoma. We identified a 98-gene signature [Signature of Peripheral Tumor-specific CD8+ T cells (SPoTT)] that discriminated circulating tumor–specific CD8+ T cells from other T cells in immunotherapy-naïve patients. We observed profound transcriptomic differences among tumor-specific CD8+ T cells from blood versus those from tumor. In validation cohorts of Merkel cell carcinoma, as well as neoantigen-driven cancers, the signature of peripheral tumor-specific CD8+ T cells was able to identify viral oncoprotein- and neoantigen-specific CD8+ T cells with both sensitivity and specificity above 75%. We also tested a previously described 151-gene signature (NeoTCRPBL) trained on neoantigen-specific CD8+ T cells and found it was able to recognize Merkel cell polyomavirus–specific T cells with a sensitivity of 66% and a specificity of 88%. These findings show that circulating tumor–specific CD8+ T cells share fundamental characteristics across diverse tumor antigen types. More broadly, insights into antitumor T cells gained from virus-driven cancers are also likely to be relevant in mutationally driven cancers.