Immune Checkpoint Inhibitors Regulate K+ Channel Activity in Cytotoxic T Lymphocytes of Head and Neck Cancer Patients
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 KC...
Saved in:
Published in | Frontiers in pharmacology Vol. 12; p. 742862 |
---|---|
Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
27.08.2021
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by:Ildikò Szabò, University of Padua, Italy This article was submitted to Pharmacology of Ion Channels and Channelopathies, a section of the journal Frontiers in Pharmacology Reviewed by:Timm Danker, University of Tübingen, Germany Hongguang Nie, China Medical University, China |
ISSN: | 1663-9812 1663-9812 |
DOI: | 10.3389/fphar.2021.742862 |