{"doi":"10.3389/fphar.2021.742862","title":"Immune Checkpoint Inhibitors Regulate K+ Channel Activity in Cytotoxic T Lymphocytes of Head and Neck Cancer Patients","abstract":"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 2+ fluxes, and thereby T cell effector functions. In HNSCC patients, PD-1 blockade increases KCa3.1 and Kv1.3 activity along with Ca 2+ signaling and mobility in CD8 + 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 2+ signaling in CD8 + 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 + PBTs of HNSCC patients. Anti-PD-1 treatment increases Ca 2+ fluxes in a subset of HSNCC patients. In CD8 + PBTs of HDs, exposure to PD-L1 reduces KCa3.1 activity and Ca 2+ 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 + PBTs, anti-PD-1 treatment did not affect the expression of KCa3.1, Kv1.3, Ca 2+ release activated Ca 2+ (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.","journal":"Frontiers in Pharmacology","year":2021,"id":190275,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"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":364967,"name":"Ameet A. Chimote","orcid":"0000-0001-5163-0123","position":1,"is_corresponding":false},{"id":364969,"name":"Hannah S. Newton","orcid":"0000-0002-6368-0803","position":2,"is_corresponding":false},{"id":754325,"name":"Manuel G. Feria-Garzón","orcid":null,"position":3,"is_corresponding":false},{"id":753887,"name":"Martina Chirra","orcid":"0000-0003-2049-8507","position":4,"is_corresponding":false},{"id":481543,"name":"Edith M. Janssen","orcid":"0000-0001-7881-6307","position":5,"is_corresponding":false},{"id":231718,"name":"Trisha M. Wise‐Draper","orcid":"0000-0002-7279-4028","position":6,"is_corresponding":false},{"id":364970,"name":"Laura Conforti","orcid":"0000-0002-3761-7595","position":7,"is_corresponding":false},{"id":364968,"name":"Vaibhavkumar S. Gawali","orcid":"0000-0002-7917-4913","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:49:22.671571Z","pmid":"34512366","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":[]}