TCR repertoire and transcriptional signatures of circulating tumour‐associated T cells facilitate effective non‐invasive cancer detection

Traditional serological tumour biomarkers like α-fetoprotein, prostate-specific antigens, carcinoembryonic antigens, CA19–9 and CA125 have been widely investigated in clinic, but the specificity has not reached a satisfactory stage for population level.1–3 Novel technologies utilizing tumour-derived signals from blood non-invasively provide a new tumour diagnostic strategy called liquid biopsy over the past decades.3–5 Several peripheral biomarkers such as cell-free DNA (cfDNA)6–8 especially circulating tumour DNA (ctDNA),9 circulating tumour cells (CTCs),10,11 circulating micro-RNAs,12,13 tumour-derived exosomes14 and cancer cell metabolites15 achieved great progress and showed huge prospects in tumour screening. The feasibility of using tumour-associated T cell response involved in tumour initiation and development, as a supplementary diagnosis choice has not been explored widely.16,17 Until recently, tumour-infiltrated T lymphocytes (TILs) were considered to be beneficial tumour-specific T cells.18 But due to the complex interaction of different immune components mediated by chemokines or cytokines within the tumour microenvironment (TME), the majority of passively expanding TILs cannot recognize tumour-specific antigens (TSAs) and are thus believed to be bystander T cells.19–21 These bystander T cells may dilute tumour-specific signals and make the identification of TSAs-specific T cells challenging.22–24 Programmed cell death protein 1 (PD-1) is suggested to be a biomarker for tumour-specific CD8+ T cells both in TILs and in peripheral blood mononuclear cells (PBMCs),22,25–27 but the efficacy needs to be further validated in practical applications.21,28,29 Tracking the general immunophenotype of T lymphocytes when they encounter antigens and enrichment of tumour-associated T cells over a pool of irrelevant signals during tumour development reflects the overall immune status of patients and offers opportunities for cancer prevention and therapy.30 Next generation sequencing (NGS)-based T cell receptor (TCR) repertoire quantification has provided methods for TSA recognition and now is extensively used in the identification of tumour-reactive T lymphocytes.19,31–34 The past few years have witnessed a series of studies utilizing T or B-cell repertoire to pinpoint disease-associated signatures, and evidences have demonstrated the diagnostic potential of TCR repertoire in autoimmune diseases,35 infectious diseases36,37 and even cancer.38–42 Sustained neoant