{"doi":"10.1101/2021.04.08.439061","title":"Immunogenicity of a public neoantigen derived from mutated <i>PIK3CA</i>","abstract":"ABSTRACT Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrent mutations in driver genes that are restricted by prevalent HLA alleles. Here, we report on a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant (Mut) PIK3CA , among the most common genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this method, we developed a library of TCRs that recognize an endogenously processed neoepitope containing a common PIK3CA hotspot mutation that is restricted by HLA-A*03:01. Mechanistically, immunogenicity to this public NeoAg arises primarily from enhanced stability of the neopeptide/HLA complex caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a relatively “featureless” surface dominated by the peptide’s backbone. To overcome the challenge of binding such an epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface aided by an unusually long β-chain complementarity-determining region 3 (CDR3β) loop. In a pan-cancer cohort of patients with diverse malignancies that express the PIK3CA public NeoAg, we observed spontaneous immunogenicity, NeoAg clonal conservation, and in a limited number of cases, evidence of targeted immune escape. Together, these results establish the immunogenic potential of Mut PIK3CA , creating a framework for off-the-shelf immunotherapies targeting this public NeoAg.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":217362,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"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":670954,"name":"Jiaqi Ma","orcid":"0000-0002-6298-0193","position":1,"is_corresponding":false},{"id":476774,"name":"Martin G. Klatt","orcid":"0000-0001-8703-7305","position":2,"is_corresponding":false},{"id":81214,"name":"Friederike Dündar","orcid":"0000-0002-2301-112X","position":3,"is_corresponding":false},{"id":271416,"name":"Chaitanya Bandlamudi","orcid":"0000-0003-1108-4919","position":4,"is_corresponding":false},{"id":90747,"name":"Pedram Razavi","orcid":"0000-0003-4236-0576","position":5,"is_corresponding":false},{"id":236121,"name":"Hannah Y. Wen","orcid":"0000-0001-6794-5234","position":6,"is_corresponding":false},{"id":244697,"name":"Britta Weigelt","orcid":"0000-0001-9927-1270","position":7,"is_corresponding":false},{"id":237940,"name":"Paul Zumbo","orcid":"0000-0001-7234-2024","position":8,"is_corresponding":false},{"id":814731,"name":"Si Ning Fu","orcid":null,"position":9,"is_corresponding":false},{"id":814197,"name":"Lauren B. Banks","orcid":"0000-0002-3443-6414","position":10,"is_corresponding":false},{"id":814732,"name":"Watchain D. Bestman","orcid":null,"position":11,"is_corresponding":false},{"id":230273,"name":"Alexander Drilon","orcid":"0000-0001-6806-9061","position":12,"is_corresponding":false},{"id":53879,"name":"Doron Betel","orcid":"0000-0002-8006-7752","position":13,"is_corresponding":false},{"id":255865,"name":"David A. Scheinberg","orcid":"0000-0002-4160-923X","position":14,"is_corresponding":false},{"id":299086,"name":"Brian M. Baker","orcid":"0000-0002-0864-0964","position":15,"is_corresponding":false},{"id":311733,"name":"Christopher A. Klebanoff","orcid":"0000-0001-9645-3896","position":16,"is_corresponding":false},{"id":488147,"name":"Smita S. Chandran","orcid":"0000-0001-9266-6878","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-18T23:53:20.374789Z","pmid":null,"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":[]}