biostudies-literatureSievers CIntramural NIH HHSNational Institute on Deafness and Other Communication DisordersNational Cancer InstituteNCI NIH HHSNational Institutes of Health887-902.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC10175181biostudies-literatureUnknown41(5)Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8⁺ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-β and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-β-driven CD103 expression on CD8⁺ T cells is reversed following TGF-β neutralization in vitro, implicating TGF-β in T cell tissue retention and impaired systemic immunity. Transcriptional changes implicate T cell receptor signaling and glutamine metabolism Cancer cellPhenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer.PMC10175181HHSN261201500003IHHSN261201500003CZIA BC012131ZIA DC000087Chari RRedman JMSievers CCraveiro MRobbins YYang XSoon-Shiong PSchlom JGulley JFriedman JBai KNguyen AAllen CTfalsePhenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer.Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8⁺ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-β and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-β-driven CD103 expression on CD8⁺ T cells is reversed following TGF-β neutralization in vitro, implicating TGF-β in T cell tissue retention and impaired systemic immunity. Transcriptional changes implicate T cell receptor signaling and glutamine metabolism 2023-01-01T00:00:00Z2023 May2026-06-01T17:26:22.921Z2026-04-08T14:12:35.988ZS-EPMC101751813705910410.1016/j.ccell.2023.03.014