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 Ca2+ fluxes, and thereby T cell effector functions. In HNSCC patients, PD-1 blockade increases KCa3.1 and Kv1.3 activity along with Ca2+ 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 Ca2+ 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 Ca2+ fluxes in a subset of HSNCC patients. In CD8+ PBTs of HDs, exposure to PD-L1 reduces KCa3.1 activity and Ca2+ 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, Ca2+ release activated Ca2+ (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.
Highlights
Head and neck squamous cell cancer (HNSCC) is the seventh most common cancer worldwide (Chow, 2020; Sung et al, 2021)
Flow cytometry experiments showed no changes in the expression of either ion channels or activation and exhaustion markers in CD8+ peripheral blood T cells (PBTs) from HNSCC patients after αPD-1 treatment (Figure 1F; Supplementary Figures S3–S4)
These findings indicate that αPD-1 treatment increases KCa3.1 and Kv1.3, but not Ca2+ release activated Ca2+ (CRAC) channel, activity in CD8+ PBTs of HNSCC patients
Summary
Head and neck squamous cell cancer (HNSCC) is the seventh most common cancer worldwide (Chow, 2020; Sung et al, 2021). Conventional treatments include surgery, radiotherapy, chemotherapy, and multimodal approaches. The prognosis of locally advanced disease remains poor, with a 5 years overall survival
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