{"doi":"10.1101/2023.05.06.539290","title":"Linked CD4 <sup>+</sup> /CD8 <sup>+</sup> T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression","abstract":"Abstract Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response of an aggressive low TMB squamous cell tumor to ICB could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4 + and CD8 + T cells. We found that, whereas vaccination with CD4 + or CD8 + NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1 + tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4 + /CD8 + T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8 + T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. The concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":396351,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"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":421071,"name":"Joey Lee","orcid":null,"position":1,"is_corresponding":false},{"id":896102,"name":"Spencer E. Brightman","orcid":"0000-0002-9930-7218","position":2,"is_corresponding":false},{"id":324395,"name":"Sara McArdle","orcid":"0000-0003-3795-3772","position":3,"is_corresponding":false},{"id":844463,"name":"Samantha M. Hall","orcid":"0000-0003-1608-9508","position":4,"is_corresponding":false},{"id":933086,"name":"Rukman R. Thota","orcid":"0000-0002-9225-9516","position":5,"is_corresponding":false},{"id":1025307,"name":"Manasa Lanka","orcid":"0000-0003-3301-7768","position":6,"is_corresponding":false},{"id":501588,"name":"Ashmitaa Logandha Ramamoorthy Premlal","orcid":"0000-0001-7110-4235","position":7,"is_corresponding":false},{"id":19878,"name":"Jason Greenbaum","orcid":"0000-0002-1381-0390","position":8,"is_corresponding":false},{"id":510055,"name":"Ezra E.W. Cohen","orcid":"0000-0002-9872-6242","position":9,"is_corresponding":false},{"id":34766,"name":"Bjoern Peters","orcid":"0000-0002-8457-6693","position":10,"is_corresponding":false},{"id":419740,"name":"Stephen P. Schoenberger","orcid":"0000-0002-9870-7340","position":11,"is_corresponding":false},{"id":419738,"name":"Joseph S. Dolina","orcid":"0000-0002-4602-8194","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:31.472087Z","pmid":"37205330","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":[]}