{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:04:05Z","timestamp":1790809445964,"version":"4.1.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Programmed death receptor-1 (PD-1) and its ligand (PD-L1) interaction negatively regulates T cell function in head and neck squamous cell carcinoma (HNSCC). Overexpression of PD-1 reduces intracellular Ca<jats:sup>2+<\/jats:sup> fluxes, and thereby T cell effector functions. In HNSCC patients, PD-1 blockade increases KCa3.1 and Kv1.3 activity along with Ca<jats:sup>2+<\/jats:sup> signaling and mobility in CD8<jats:sup>+<\/jats:sup> peripheral blood T cells (PBTs). The mechanism by which PD-L1\/PD-1 interaction regulates ion channel function is not known. We investigated the effects of blocking PD-1 and PD-L1 on ion channel functions and intracellular Ca<jats:sup>2+<\/jats:sup> signaling in CD8<jats:sup>+<\/jats:sup> PBTs of HNSCC patients and healthy donors (HDs) using single-cell electrophysiology and live microscopy. Anti-PD-1 and anti-PD-L1 antibodies increase KCa3.1 and Kv1.3 function in CD8<jats:sup>+<\/jats:sup> PBTs of HNSCC patients. Anti-PD-1 treatment increases Ca<jats:sup>2+<\/jats:sup> fluxes in a subset of HSNCC patients. In CD8<jats:sup>+<\/jats:sup> PBTs of HDs, exposure to PD-L1 reduces KCa3.1 activity and Ca<jats:sup>2+<\/jats:sup> signaling, which were restored by anti-PD-1 treatment. The PD-L1-induced inhibition of KCa3.1 channels was rescued by the intracellular application of the PI3 kinase modulator phosphatidylinositol 3-phosphate (PI3P) in patch-clamp experiments. In HNSCC CD8<jats:sup>+<\/jats:sup> PBTs, anti-PD-1 treatment did not affect the expression of KCa3.1, Kv1.3, Ca<jats:sup>2+<\/jats:sup> release activated Ca<jats:sup>2+<\/jats:sup> (CRAC) channels, and markers of cell activation (CD69) and exhaustion (LAG-3 and TIM-3). Our data show that immune checkpoint blockade improves T cell function by increasing KCa3.1 and Kv1.3 channel activity in HNSCC patients.<\/jats:p>","DOI":"10.3389\/fphar.2021.742862","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T15:15:28Z","timestamp":1630941328000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Immune Checkpoint Inhibitors Regulate K+ Channel Activity in Cytotoxic T Lymphocytes of Head and Neck Cancer Patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Vaibhavkumar S.","family":"Gawali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ameet A.","family":"Chimote","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah S.","family":"Newton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel G.","family":"Feria-Garz\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Chirra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith M.","family":"Janssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha M.","family":"Wise-Draper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Conforti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"561","DOI":"10.3389\/fphar.2017.00561","article-title":"PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome","volume":"8","author":"Alsaab","year":"2017","journal-title":"Front. 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