Hypoxia and Potassium Channel Activity in T Lymphocytes

 描述(申请人提供)：由于实体肿瘤中氧气供应减少(缺氧)和腺苷积累，肿瘤微环境与免疫监测的失败和基于免疫的治疗效果有限有关。缺氧和腺苷都强烈抑制肿瘤浸润性淋巴细胞(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Ca~(2+)内流的离子通道，而Ca~(2+)内流对T淋巴细胞的激活和功能至关重要。具体地说，两个钾通道Kv1.3和KCa3.1通过钙通道调节钙离子内流的驱动力而发挥关键作用。多年来，我们研究了低氧和腺苷对健康个体循环T淋巴细胞离子通道的影响。我们已经证明低氧通过Kv1.3抑制T细胞的增殖和细胞因子的释放。此外，腺苷通过选择性抑制KCa3.1来抑制细胞的运动。腺苷抑制KCa3.1与T细胞运动性降低之间的联系机制尚不清楚。此外，目前还没有关于癌症患者的TIL中是否存在Kv1.3和Kca3.1改变的信息。因此，在目前的应用中，我们将检验这一假设，即肿瘤微环境对T淋巴细胞钾通道的抑制导致免疫系统无法侵袭肿瘤和对抗癌细胞。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TIL中离子通道的下调是否导致它们无法产生运动和效应器功能所需的适当的钙反应。拟议中的研究结果将为实体肿瘤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.