{"doi":"10.1136/jitc-2020-000844","title":"PD1 blockade enhances K<sup>+</sup> channel activity, Ca<sup>2+</sup> signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer","abstract":"Background Immunotherapy has emerged as a promising treatment modality for head and neck squamous cell carcinoma (HNSCC). Pembrolizumab, an anti-programmed death 1 antibody, is an immunotherapy agent currently approved for metastatic HNSCC and curative intent clinical trials. Although clinical responses to pembrolizumab are promising, many patients fail to respond. However, it is well known that T cell cytotoxicity and chemotaxis are critically important in the elimination of HNSCC tumors. These functions depend on ion channel activity and downstream Ca 2+ fluxing abilities, which are defective in patients with HNSCC. The purpose of this study was to elucidate the effects of pembrolizumab on potassium (K + ) channel (KCa3.1 and Kv1.3) activity, Ca 2+ fluxes, and chemotaxis in the cytotoxic T cells of patients with HNSCC and to determine their correlation with treatment response. Methods Functional studies were conducted in CD8 + peripheral blood T cells (PBTs) and tumor infiltrating lymphocytes (TILs) from patients with HNSCC treated with pembrolizumab. Untreated patients with HNSCC were used as controls. The ion channel activity of CD8 + T cells was measured by patch-clamp electrophysiology; single-cell Ca 2+ fluxing abilities were measured by live microscopy. Chemotaxis experiments were conducted in a three-dimensional collagen matrix. Pembrolizumab patients were stratified as responders or non-responders based on pathological response (percent of viable tumor remaining at resection; responders: ≤80% viable tumor; non-responders: &gt;80% viable tumor). Results Pembrolizumab increased K + channel activity and Ca 2+ fluxes in TILs independently of treatment response. However, in PBTs from responder patients there was an increased KCa3.1 activity immediately after pembrolizumab treatment that was accompanied by a characteristic increase in Kv1.3 and Ca 2+ fluxes as compared with PBTs from non-responder patients. The effects on Kv1.3 and Ca 2+ were prolonged and persisted after tumor resection. Chemotaxis was also improved in responder patients’ PBTs. Unlike non-responders’ PBTs, pembrolizumab increased their ability to chemotax in a tumor-like, adenosine-rich microenvironment immediately after treatment, and additionally they maintained an efficient chemotaxis after tumor resection. Conclusions Pembrolizumab enhanced K + channel activity, Ca 2+ fluxes and chemotaxis of CD8 + T cells in patients with HNSCC, with a unique pattern of response in responder patients that is conducive to the heightened functionality of their cytotoxic T cells.","journal":"Journal for ImmunoTherapy of Cancer","year":2020,"id":97388,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.96,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":364968,"name":"Vaibhavkumar S. Gawali","orcid":"0000-0002-7917-4913","position":1,"is_corresponding":false},{"id":364967,"name":"Ameet A. Chimote","orcid":"0000-0001-5163-0123","position":2,"is_corresponding":false},{"id":481540,"name":"Maria Lehn","orcid":"0000-0001-8400-7733","position":3,"is_corresponding":false},{"id":445571,"name":"Sarah Palackdharry","orcid":"0000-0002-6394-8080","position":4,"is_corresponding":false},{"id":481541,"name":"Benjamin H. Hinrichs","orcid":"0000-0001-9074-1205","position":5,"is_corresponding":false},{"id":481542,"name":"Roman Jandarov","orcid":"0000-0003-2145-045X","position":6,"is_corresponding":false},{"id":270445,"name":"David A. Hildeman","orcid":"0000-0002-0421-8483","position":7,"is_corresponding":false},{"id":481543,"name":"Edith M. Janssen","orcid":"0000-0001-7881-6307","position":8,"is_corresponding":false},{"id":231718,"name":"Trisha M. Wise‐Draper","orcid":"0000-0002-7279-4028","position":9,"is_corresponding":false},{"id":364970,"name":"Laura Conforti","orcid":"0000-0002-3761-7595","position":10,"is_corresponding":false},{"id":364969,"name":"Hannah S. Newton","orcid":"0000-0002-6368-0803","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T22:35:34.520494Z","pmid":"33060146","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":[]}