{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T12:30:27Z","timestamp":1781353827730,"version":"3.54.1"},"reference-count":78,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA277493-02"],"award-info":[{"award-number":["R01CA277493-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Donor lymphocyte infusion (DLI) is commonly used to prevent or treat leukemic relapse following allogeneic hematopoietic cell transplantation; however, efficacy is limited by immune exhaustion, checkpoint-mediated inhibition, and the risk of graft-versus-host disease (GvHD). Gamma delta (\u03b3\u03b4) T-cells represent a promising \u201coff-the-shelf\u201d adoptive cell therapy (ACT) with favorable safety and MHC-independent cytotoxicity, yet their function is similarly constrained by the leukemic tumor microenvironment (TME). Acute exercise mobilizes cytotoxic lymphocyte subsets, and is an emerging strategy to enhance cellular immunotherapies, including DLI and expanded \u03b3\u03b4 T-cells. This study examined how exercise-mobilized lymphocytes and exercise-expanded \u03b3\u03b4 T-cells interact with TIGIT blockade to improve anti-leukemic activity. Methods: Healthy participants completed an acute cycling bout, after which peripheral blood mononuclear cells (PBMCs) and ex vivo expanded \u03b3\u03b4 T-cells were phenotyped and cytotoxicity was determined against leukemia cells with TIGIT checkpoint inhibition. The therapeutic relevance of combining TIGIT blockade with rest- or exercise-expanded \u03b3\u03b4 T-cells was further evaluated in NSG-IL15 mice challenged with K562-luc leukemia. Results: Acute exercise increased circulating CD8+ and \u03b3\u03b4 T-cells with higher TIGIT and PD-1 expression. Exercise-expanded \u03b3\u03b4 T-cells maintained increased PD-1 and TIGIT expression and exhibited increased co-expression of DNAM-1 and TIGIT. Exercise mobilized PBMCs and exercise-expanded \u03b3\u03b4 T-cells demonstrated enhanced cytotoxicity, further amplified by TIGIT blockade. In vivo, TIGIT-treated exercise-expanded \u03b3\u03b4 T-cells modestly improved tumor suppression and prolonged tumor-free survival compared to untreated controls. Conclusions: Exercise primes DLI and \u03b3\u03b4 T-cell products for enhanced responsiveness to TIGIT checkpoint inhibition. Targeting TIGIT likely augments DNAM-1 dependent cytotoxicity and improves anti-leukemic activity, supporting the integration of exercise-enhanced DLI and \u03b3\u03b4 T-cell therapies with immune checkpoint blockade as a safe strategy to improve relapse control in leukemia.<\/jats:p>","DOI":"10.3390\/cancers18050797","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T16:18:45Z","timestamp":1772554725000},"page":"797","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["TIGIT Blockade Potentiates the Anti-Leukemic Activity of Exercise-Mobilized Donor Lymphocytes and Expanded \u03b3\u03b4 T-Cells"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0170-5593","authenticated-orcid":false,"given":"Grace M.","family":"McKenzie","sequence":"first","affiliation":[{"name":"School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josie","family":"Voss","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-6965","authenticated-orcid":false,"given":"Emmanuel","family":"Katsanis","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"},{"name":"University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7064-6881","authenticated-orcid":false,"given":"Richard J.","family":"Simpson","sequence":"additional","affiliation":[{"name":"School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"},{"name":"University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5338-7905","authenticated-orcid":false,"given":"Forrest L.","family":"Baker","sequence":"additional","affiliation":[{"name":"School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"},{"name":"University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Exercise Science, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/s41409-020-01163-z","article-title":"Relapse of acute myeloid leukemia after allogeneic hematopoietic cell transplantation: Clinical features and outcomes","volume":"56","author":"Yanada","year":"2021","journal-title":"Bone Marrow Transpl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.hemonc.2020.11.006","article-title":"Survival following relapse after allogeneic hematopoietic cell transplantation for acute leukemia and myelodysplastic syndromes in the contemporary era","volume":"14","author":"Hong","year":"2021","journal-title":"Hematol. 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