{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE179nnn/GSE179994/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE179994"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Temporal single cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer","description":"Immune-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.","dates":{"publication":"2021/10/06"},"accession":"GSE179994","cross_references":{"GSM":["GSM5444642","GSM5444620","GSM5444643","GSM5444621","GSM5444644","GSM5444622","GSM5444645","GSM5444623","GSM5444640","GSM5444641","GSM5444628","GSM5444606","GSM5444607","GSM5444629","GSM5444608","GSM5444609","GSM5444624","GSM5444646","GSM5444647","GSM5444625","GSM5444604","GSM5444648","GSM5444626","GSM5444627","GSM5444605","GSM5444649","GSM5444631","GSM5444610","GSM5444632","GSM5444633","GSM5444611","GSM5444634","GSM5444612","GSM5444650","GSM5444630","GSM5444639","GSM5444617","GSM5444618","GSM5444619","GSM5444613","GSM5444635","GSM5444636","GSM5444614","GSM5444637","GSM5444615","GSM5444616","GSM5444638"],"GPL":["24676"],"GSE":["179994"],"taxon":["Homo sapiens"],"PMID":["[35121991]"]}}