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

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 (T_EM) 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% T_EM 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.