SEP 20, 2018 09:00 AM PDT

Defects in potassium channels contribute to reduced immune surveillance in cancers

Speakers
  • Research Associate, University of Cincinnati, Department of Internal Medicine, Division of Nephrology, Cincinnati OH
    Biography
      Ameet is currently a Research Associate in Dr. Laura Conforti's laboratory at the University of Cincinnati, where he studies the role of ion channels in T lymphocyte function, primarily in the context of solid tumors. He obtained his degree in Medicine from the University of Nagpur, India and completed his doctoral training where he studied ion transport physiology in disease causation under the guidance of Dr. Peter Lauf at Wright State University in Dayton Ohio. Subsequently, Ameet joined Dr. Conforti's laboratory as a postdoctoral fellow where he optimized the methodology for isolating tumor infiltrating lymphocytes from head and neck squamous cell tumors and developed various flow cytometry and microscopy based assays to detect ion channel function in blood and biopsy specimens from cancer patients. Ameet then transitioned to the position of Research Associate in Dr. Conforti's laboratory in 2015 and is currently continuing with his translational research. In addition to his research responsibilities in Dr. Conforti's laboratory, Ameet is also passionate about mentoring young STEM students in the laboratory and about science communication and outreach.

    Abstract:
    DATE: September 20, 2018
    TIME: 09:00am PDT, 12:00pm EDT
     
    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.

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