GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE179nnn/GSE179994/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE179994GEOGSEfalseTemporal single cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancerImmune-checkpoint therapies have shown unprecedented clinical success in the treatment of non-small-cell lung cancer, but the underlying mechanisms of anti-PD-1–induced tumour rejection remain incompletely understood. Here, we performed temporal single-cell RNA and paired T cell receptor sequencing on 47 clinical tumour biopsies from 36 non-small-cell lung cancer patients before and during combination therapies of PD-1 blockade with chemotherapy. We found that the treatment in responsive tumours preferentially increased the precursors of exhausted T cells (Tex), characterized by the low expression of co-inhibitory molecules and high expression of GZMK. By contrast, non-responsive tumours failed to accumulate Tex precursors (Texp), suggestive of the critical role of such cells in PD-1-based immunotherapies. Although these post-treatment Texp cells shared clonotypes extensively with terminal Tex subset prior to treatment, our data suggested that they were not derived from the reinvigoration of terminal Tex cells; instead, such Texp cells were likely accumulated by (i) the expansion of pre-existing Texp cells, and (ii) the replenishment with peripheral T cells, a phenomenon we named clonal revival. Furthermore, post-treatment Texp cells expressed high level of CXCL13, which was exclusively expressed by terminal Tex subset in treatment-naïve tumours, implying that the emergence of CXCL13-expressing Texp cells resulted from the blockade of the transition to terminal Tex cells by PD-1 antibodies. Our study provides new insights into mechanisms underlying PD-1-based therapies, implicating both clonal revival and expansion of Texp cells as steps to enhance the clinical response of lung cancer patients.2021/10/06GSE179994GSM5444642GSM5444620GSM5444643GSM5444621GSM5444644GSM5444622GSM5444645GSM5444623GSM5444640GSM5444641GSM5444628GSM5444606GSM5444607GSM5444629GSM5444608GSM5444609GSM5444624GSM5444646GSM5444647GSM5444625GSM5444604GSM5444648GSM5444626GSM5444627GSM5444605GSM5444649GSM5444631GSM5444610GSM5444632GSM5444633GSM5444611GSM5444634GSM5444612GSM5444650GSM5444630GSM5444639GSM5444617GSM5444618GSM5444619GSM5444613GSM5444635GSM5444636GSM5444614GSM5444615GSM5444637GSM5444616GSM544463824676179994Homo sapiens[35121991]