Phenotypic signatures of circulating neoantigen-reactive CD8+ T cells in patients with metastatic cancers

Abstract

Circulating Tcells from peripheral blood (PBL) can provide a rich and noninvasive source for antitumor Tcells. By single-cell transcriptomic profiling of 36 neoantigen-specific Tcell clones from 6 metastatic cancer patients, we report the transcriptional and cell surface signatures of antitumor PBL-derived CD8+ Tcells (NeoTCRPBL). Comparison of tumor-infiltrating lymphocyte (TIL)- and PBL-neoantigen-specific Tcells revealed that NeoTCRPBL Tcells are low in frequency and display less-dysfunctional memory phenotypes relative to their TIL counterparts. Analysis of 100 antitumor TCR clonotypes indicates that most NeoTCRPBL populations target the same neoantigens as TILs. However, NeoTCRPBL TCR repertoire is only partially shared with TIL. Prediction and testing of NeoTCRPBL signature-derived TCRs from PBL of 6 prospective patients demonstrate high enrichment of clonotypes targeting tumor mutations, a viral oncogene, and patient-derived tumor. Thus, the NeoTCRPBL signature provides an alternative source for identifying antitumor Tcells from PBL of cancer patients, enabling immune monitoring and immunotherapies.