{"doi":"10.1038/s41586-021-03752-4","title":"Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers","abstract":"Abstract PD-1 blockade unleashes CD8 T cells 1 , including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens 2 , and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay 3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIT high TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.","journal":"Nature","year":2021,"id":145267,"datarank":0.9481152441375875,"base_score":6.320768294250582,"endowment":6.320768294250582,"self_citation_contribution":0.9481152441375875,"citation_network_contribution":0.0,"self_endowment_contribution":0.9481152441375875,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":555,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":490805,"name":"Jiajia Zhang","orcid":"0000-0003-4623-6134","position":1,"is_corresponding":false},{"id":233093,"name":"Zhicheng Ji","orcid":"0000-0002-9457-4704","position":2,"is_corresponding":false},{"id":502972,"name":"Ajay Vaghasia","orcid":"0000-0002-4498-0966","position":3,"is_corresponding":false},{"id":615677,"name":"Boyang Zhang","orcid":"0000-0002-4702-7628","position":4,"is_corresponding":false},{"id":615678,"name":"Emily Han-Chung Hsiue","orcid":"0000-0001-5882-5142","position":5,"is_corresponding":false},{"id":615679,"name":"Brian J. 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Cottrell","orcid":"0000-0003-2952-1830","position":12,"is_corresponding":false},{"id":615680,"name":"Haidan Guo","orcid":"0009-0000-9678-1777","position":13,"is_corresponding":false},{"id":256932,"name":"Hok Yee Chan","orcid":null,"position":14,"is_corresponding":false},{"id":617041,"name":"Dipika Singh","orcid":null,"position":15,"is_corresponding":false},{"id":617042,"name":"Sampriti Thapa","orcid":null,"position":16,"is_corresponding":false},{"id":615681,"name":"Arbor G. Dykema","orcid":"0000-0001-5835-3261","position":17,"is_corresponding":false},{"id":617043,"name":"Poromendro Burman","orcid":null,"position":18,"is_corresponding":false},{"id":617044,"name":"Begum Choudhury","orcid":null,"position":19,"is_corresponding":false},{"id":615682,"name":"Luis Aparicio","orcid":"0000-0002-8016-0455","position":20,"is_corresponding":false},{"id":563093,"name":"Laurene S. 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