{"doi":"10.1126/sciimmunol.adj5792","title":"Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion","abstract":"Peptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed a PC-CAR targeting a neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of the PC-CAR–PHOX2B–HLA-A*24:02–β 2 m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). This PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactive group, covering a combined global population frequency of up to 46.7%. Biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation, and CAR T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes.","journal":"Science Immunology","year":2023,"id":334910,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"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":368230,"name":"Tyler J. Florio","orcid":null,"position":1,"is_corresponding":false},{"id":1038175,"name":"S. K. Gupta","orcid":"0000-0002-2151-9018","position":2,"is_corresponding":false},{"id":1038173,"name":"Michael C. Young","orcid":"0000-0002-8420-2149","position":3,"is_corresponding":false},{"id":636904,"name":"Quinlen F. Marshall","orcid":"0000-0002-4736-9716","position":4,"is_corresponding":false},{"id":843587,"name":"Samuel E. Garfinkle","orcid":"0000-0001-7729-9299","position":5,"is_corresponding":false},{"id":1063863,"name":"Georgia Papadaki","orcid":"0000-0003-0630-2248","position":6,"is_corresponding":false},{"id":636907,"name":"Hau V. Truong","orcid":"0000-0002-0059-2793","position":7,"is_corresponding":false},{"id":1063864,"name":"Emily Mycek","orcid":"0009-0000-1919-3648","position":8,"is_corresponding":false},{"id":1050698,"name":"Peiyao Li","orcid":"0000-0001-9119-2498","position":9,"is_corresponding":false},{"id":289102,"name":"Alvin Farrel","orcid":"0000-0003-1087-9840","position":10,"is_corresponding":false},{"id":636909,"name":"Nicole L. Church","orcid":"0000-0001-9551-8125","position":11,"is_corresponding":false},{"id":1064331,"name":"Shereen Jabar","orcid":null,"position":12,"is_corresponding":false},{"id":1063865,"name":"Matthew D. Beasley","orcid":"0000-0002-6046-8516","position":13,"is_corresponding":false},{"id":636911,"name":"Ben R. Kiefel","orcid":"0009-0000-4830-8221","position":14,"is_corresponding":false},{"id":289100,"name":"Mark Yarmarkovich","orcid":"0000-0003-4638-2019","position":15,"is_corresponding":false},{"id":555406,"name":"Leena Mallik","orcid":"0000-0002-5979-7494","position":16,"is_corresponding":false},{"id":240511,"name":"John M. Maris","orcid":"0000-0002-8088-7929","position":17,"is_corresponding":false},{"id":314926,"name":"Nikolaos G. Sgourakis","orcid":"0000-0003-3655-3902","position":18,"is_corresponding":false},{"id":1038172,"name":"Yi Sun","orcid":"0000-0002-7821-4346","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-19T01:09:53.742667Z","pmid":"38039376","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":[]}