{"doi":"10.1093/jimmun/vkaf139","title":"Isolation of mitochondrial mutation-specific T cell receptors","abstract":"Neoantigen-specific T cells play a major role in cancer immunotherapy. Mutated proteins derived from non-synonymous mutations in tumor genomic DNA are the major source of neoantigens. It is conceivable that non-synonymous mutations found in tumor mitochondrial DNA (mtDNA) can also generate neoantigens that can be recognized by T cell receptors (TCRs). However, no tumor mitochondrial mutation-specific TCRs have been reported. As a proof-of-concept study, we obtained 3,798 non-synonymous single-nucleotide mutations across 38 tumor types through The Cancer Mitochondria Atlas project. These mutations were subjected to an epitope prediction algorithm to predict binding affinities for HLA-A*0201. The top 300 candidate peptides were synthesized and screened against 10 healthy donors with homozygous HLA-A*0201 alleles. Mutation-reactive T cells were subjected to single-cell sequencing to identify TCR sequences, followed by validations. Here, four MT-ND2 (A103T) mutation-specific TCRs were isolated from a donor. These TCRs interacted with HLA-A*0201-restricted IMMAMTMKL peptide. Additionally, through a single-cell sequencing approach, we demonstrated that a non-synonymous mutation, MT-CO1 (V274I), could be detected in nearly all tumor cells in a colorectal tumor specimen, whereas other mutations in 2 out of 4 tumors were detected in subclonal populations. This study suggests that isolating tumor mitochondrial mutation-specific TCRs is possible, but some biological barriers need to be considered.","journal":"The Journal of Immunology","year":2025,"id":523735,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"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":1396643,"name":"Shanshan Hao","orcid":"0009-0000-8460-5653","position":1,"is_corresponding":false},{"id":586288,"name":"Charles M. Quick","orcid":null,"position":2,"is_corresponding":false},{"id":556148,"name":"Steven R. Post","orcid":"0000-0002-4711-1723","position":3,"is_corresponding":false},{"id":408702,"name":"Yuet‐Kin Leung","orcid":"0000-0003-2063-277X","position":4,"is_corresponding":false},{"id":719527,"name":"Lyle Burdine","orcid":"0000-0002-5892-2281","position":5,"is_corresponding":false},{"id":585528,"name":"Yong‐Chen Lu","orcid":"0000-0002-0275-9825","position":6,"is_corresponding":false},{"id":537960,"name":"Catherine Kirkpatrick","orcid":"0009-0000-4955-2410","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:50:07.396155Z","pmid":"40587813","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}