Hypoxia and Potassium Channel Activity in T Lymphocytes

 描述（由申请人提供）：由于实体瘤中出现的氧可用性降低（缺氧）和腺苷蓄积，肿瘤微环境与免疫监视失败和基于免疫的治疗的疗效有限有关。缺氧和腺苷都强烈抑制肿瘤浸润淋巴细胞（TIL）的功能，限制了它们驱动肿瘤消除的能力。T淋巴细胞的功能依赖于控制Ca2+内流的离子通道，这对于这些免疫细胞的激活和功能至关重要。特别是两个钾通道，Kv1.3和KCa3.1，通过调节Ca2+通过Ca2+通道内流的驱动力发挥关键作用。多年来，我们研究了缺氧和腺苷对健康人循环T淋巴细胞离子通道的影响。我们已经表明，缺氧抑制T细胞增殖和细胞因子释放通过Kv1.3。此外，腺苷通过选择性抑制KCa 3.1来抑制细胞运动。腺苷抑制KCa 3.1与T细胞运动性降低之间的联系机制尚不清楚。此外，没有关于Kv1.3和KCa3.1的改变是否存在于癌症患者的TIL中的信息。因此，在本申请中，我们将测试肿瘤微环境对T淋巴细胞中钾通道的抑制导致免疫系统无法侵入肿瘤块并对抗癌细胞的假设。我们将进行实验，以确定腺苷抑制T细胞运动的离子机制。此外，我们将研究肿瘤微环境对TILs中离子通道的下调是否导致TILs无法产生运动性和效应器功能所需的适当Ca2+反应。拟议研究的结果将为实体瘤中免疫监视减少的机制提供新的见解。这些数据对于开发旨在减少肿瘤免疫逃逸的新疗法至关重要。

 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.