{"doi":"10.1136/jitc-2023-007288","title":"Neoantigen-specific CD4<sup>+</sup> tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients","abstract":"Background Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4 + T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress. Methods We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT. Results We discovered that neoantigen-specific TIL clones were predominantly CD4 + T cells and were present in both therapeutic responders and non-responders. CD4 + TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4 + TIL. Conclusions Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4 + T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4 + TIL in future ACT protocols as a strategy to improve antitumor immunity.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":323770,"datarank":0.5416376868966337,"base_score":3.6109179126442243,"endowment":3.6109179126442243,"self_citation_contribution":0.5416376868966337,"citation_network_contribution":0.0,"self_endowment_contribution":0.5416376868966337,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":318017,"name":"Jamie K. 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