Hypoxia and Potassium Channel Activity in T Lymphocytes

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 DESCRIPTION (provided by applicant): The tumor microenvironment has been implicated in the failure of immune surveillance and the limited efficacy of immune based therapies due to the decreased oxygen availability (hypoxia) and accumulation of adenosine that occur in solid tumors. Both hypoxia and adenosine strongly inhibit the function of tumor infiltrating lymphocytes (TIL) limiting their ability to drive tumor elimination. The functionality of T lymphocytes relies on ion channels that control Ca2+ influx which is essential for the activation and function of these immune cells. Specifically two potassium channels, Kv1.3 and KCa3.1, play critical roles by regulating the driving force for Ca2+ influx through Ca2+ channels. Over the years we have investigated the effects of hypoxia and adenosine on ion channels in circulating T lymphocytes from healthy individuals. We have shown that hypoxia suppresses T cell proliferation and cytokine release via Kv1.3. Furthermore, adenosine inhibits the motility of cells via selective inhibition of KCa3.1. The mechanisms that link adenosine's inhibition of KCa3.1 to reduced T cell motility are not understood. Moreover, no information is available as to whether alterations in Kv1.3 and KCa3.1 are present in TILs from cancer patients. Therefore, in the current application we will test the hypothesis that inhibition of potassium channels in T lymphocytes by the tumor microenvironment contributes to the failure of the immune system to invade the tumor mass and fight cancer cells. We will perform experiments to identify the ionic mechanisms by which adenosine suppresses T cell motility. Furthermore, we will study whether the down regulation of ion channels in TILs by the tumor microenvironment contributes to their inability to develop the appropriate Ca2+ responses necessary for motility and effector functions. Findings from the proposed studies will provide new insights into the mechanisms involved in decrease immune surveillance in solid tumors. Such data are critical to develop new therapies aimed to reduce tumor immune escape.