Defects in potassium channels contribute to reduced immune surveillance in cancers

Sponsored by: Thermo Fisher Scientific/Gibco

Speaker

Ameet Chimote, PhD

Research Scientist, University of Cincinnati, Department of Internal Medicine, Division of Nephrology, Cincinnati OH
BIOGRAPHY

Event Date & Time

DATE: September 20, 2018

TIME: 09:00am PDT, 12:00pm EDT

Abstract

Harnessing the immune system has emerged as a powerful therapeutic strategy in oncology. However, the limited ability of cytotoxic CD8+ T cells to infiltrate solid tumors presents a major roadblock to develop effective immunotherapy. Cytotoxic CD8+ T cells, in fact, have to infiltrate solid tumors, attack and kill cancer cells in order to provide an effective antitumor response. CD8+ T cell effector functions depend on Ca2+ influx into the T cell, which is controlled by two potassium (K+) channels: the voltage-dependent Kv1.3 and the Ca2+-activated KCa3.1. Our laboratory studies the contribution of these channels to T cell effector functions in patients with head and neck squamous cell carcinoma (HNSCC). We recently reported a decreased Kv1.3 function accompanied by a decrease in Ca2+ influx in tumor infiltrating lymphocytes (TILs) isolated from HNSCC patients. Furthermore, CD8+ TILs expressing high Kv1.3 levels and showing increased cell proliferation and cytotoxicity preferentially accumulated in the stroma. We also reported a role for K+ channels in regulating CD8+ T cell infiltration in tumors. Various intratumoral factors, especially the nucleoside adenosine limit the accumulation of TILs. We analyzed the migration of CD8+ T cells from HNSCC patients using a 3D chemotaxis assay and observed that adenosine inhibited the chemotaxis of CD8+ T cells from HNSCC patients to a greater degree than CD8+ T cells from healthy individuals. This increased sensitivity of HNSCC CD8+ T cells to adenosine correlated with their inability to infiltrate the tumor and was due to a decrease in KCa3.1 activity. Thus, our data indicate that defects in the K+ channels in T cells limit their effector functions and migration into the tumors, thereby contributing to the reduced anti-tumor immune response. Positive modulators of these channels could improve cancer immune surveillance, thus potentially opening new avenues for cancer immunotherapy.

Learning Objectives:

Understanding the physiological role of Kv1.3 and KCa3.1 channels in T cell function and learn how their defective function in cancer T cells can lead to decreased immune anti-tumor response
Learn about the various experimental methodologies and functional assays to assess T cell function.