Kv1.3 Channels Mark Functionally Competent CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Cancer

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Abstract
Tumor-infiltrating lymphocytes (TIL) are potent mediators of an antitumor response. However, their function is attenuated in solid tumors. CD8+ T-cell effector functions, such as cytokine and granzyme production, depend on cytoplasmic Ca2+, which is controlled by ion channels. In particular, Kv1.3 channels regulate the membrane potential and Ca2+ influx in human effector memory T (TEM) cells. In this study, we assessed the contribution of reduced Kv1.3 and Ca2+ flux on TIL effector function in head and neck cancer (HNC). We obtained tumor samples and matched peripheral blood from 14 patients with HNC. CD3+ TILs were composed of 57% CD4+ (82% TEM and 20% Tregs) and 36% CD8+ cells. Electrophysiology revealed a 70% reduction in functional Kv1.3 channels in TILs as compared with peripheral blood T cells from paired patients, which was accompanied by a decrease in Ca2+ influx. Immunofluorescence analysis showed that CD8+ TILs expressing high Kv1.3 preferentially localized in the stroma. Importantly, high expression of Kv1.3 correlated with high Ki-67 and granzyme B expression. Overall, these data indicate that defective Kv1.3 channels and Ca2+ fluxes in TILs may contribute to reduced immune surveillance in HNC. Cancer Res; 77(1); 53–61. ©2016 AACR.

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