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.

Defects in potassium channels contribute to reduced immune surveillance in cancers

Defects in potassium channels contribute to reduced immune surveillance in cancers

Ameet Chimote, PhD

Defects in potassium channels contribute to reduced immune surveillance in cancers