{"doi":"10.1136/jitc-2024-011351","title":"Selection of therapeutically effective T-cell receptors from the diverse tumor-bearing repertoire","abstract":"Background The development of T-cell receptor (TCR)-based T-cell therapies is hampered by the difficulties in identifying therapeutically effective tumor-specific TCRs from the natural repertoire of a patient’s cancer-specific T cells. Methods Here, we mimic experimentally near-patient conditions to analyze the T-cell repertoire in euthymic tumor-bearing mice responding to the H-2K b -presented neoantigen p68 S551F (mp68). We temporarily separated the time point of mp68 expression from that of cancer cell transplantation to exclude the influence of injection-induced inflammation on T-cell priming. Thus, the mp68-specific T-cell response could only develop after the acute inflammatory phase had subsided. Results We found that mp68-specific TCRs isolated from either tumor-infiltrating T cells or spleens of mice immunized with mp68-expressing cancer cells are diverse and not inherently therapeutic when introduced into peripheral T cells and used for adoptive therapy of established tumors. While measuring short-term T-cell responses in vitro was unreliable for some TCRs in predicting their therapeutic failure, assessing the persistence of cancer cell destruction by TCR-modified T cells in long-term cultures accurately predicted therapeutic outcomes. A tumor-derived TCR with optimal function was also correctly identified with this approach when analyzing human TCRs that recognize the HLA-A2-presented neoantigen CDK4 R24L . Conclusions We show that a neoantigen-directed T-cell response in tumor-bearing hosts comprises a diverse repertoire. Infiltration and expansion of certain T-cell clonotypes in the tumor do not necessarily correlate with therapeutic efficacy of their TCRs in adoptive therapy. We propose that analysis of persistent rather than immediate responses of TCR-modified T cells in vitro serves as a reliable parameter to identify TCRs that are therapeutically effective in vivo.","journal":"Journal for ImmunoTherapy of Cancer","year":2025,"id":531397,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1377108,"name":"Leo Hansmann","orcid":"0000-0003-3790-0128","position":1,"is_corresponding":false},{"id":392166,"name":"Vasiliki Anastasopoulou","orcid":"0009-0008-0620-2910","position":2,"is_corresponding":false},{"id":441176,"name":"Steven P. 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