Hypoxia and Potassium Channel Activity in T Lymphocytes

描述（由申请人提供）：在实体瘤中可能会遇到氧气可用性降低（缺氧），并且与不良预后相关。缺氧可以直接或通过腺苷的积累影响许多参与肿瘤形成的细胞的功能。缺氧和腺苷都被证明会抑制肿瘤浸润淋巴细胞的功能，从而导致免疫系统对抗癌细胞的失败。T淋巴细胞的功能依赖于控制钙（Ca2+）内流的离子通道，这对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+内流的驱动力，在Ca2+反应的发展和持续中发挥关键作用。我们已经证明，缺氧选择性地抑制Kv1.3通道的功能和表达，减少T细胞增殖和细胞因子释放。在缺氧时介导Kv1.3表达下调的机制尚不完全清楚。此外，腺苷是否对这些重要通道有任何影响并通过它们调节T细胞功能尚无信息。我们已经获得了腺苷抑制KCa3.1通道活性的初步证据。因此，在当前的应用中，我们将验证实体肿瘤的微环境，特别是缺氧和腺苷，抑制Kv1.3和KCa3.1通道对T细胞产生多向攻击，从而削弱免疫防御的假设。我们将通过实验来确定在缺氧条件下介导Kv1.3表达下调的机制。此外，我们将研究缺氧时KCa3.1抑制的信号通路及其功能相关性。我们还将设计多价纳米颗粒来选择性地靶向与腺苷降低免疫功能有关的分子表达。所提出的研究结果将为实体瘤中免疫监视降低的机制提供新的见解。此外，它们将提供新的治疗靶点和方法，以维持免疫细胞在缺氧微环境中对抗癌细胞的能力。公共卫生相关性：免疫系统的功能之一是攻击癌细胞并摧毁它们。不幸的是，肿瘤中的特殊情况会抑制免疫细胞这样做的能力。我们建议研究这些条件对免疫细胞膜离子通道的影响如何导致免疫系统破坏癌细胞的失败。

DESCRIPTION (provided by applicant): A decrease in oxygen availability (hypoxia) can be encountered in solid tumors and has been associated with a poor outcome. Hypoxia can affect the function of many cells involved in tumor formation either directly or through the accumulation of adenosine. Both hypoxia and adenosine have been shown to inhibit the function of tumor infiltrating lymphocytes thus contributing to the failure of the immune system to fight cancer cells. The functionality of T lymphocytes relies on ion channels that control calcium (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 in the development and persistence of the Ca2+ response by regulating the driving force for Ca2+ influx. We have shown that hypoxia selectively inhibits the function and expression of Kv1.3 channels and decreases T cell proliferation and cytokine release. The mechanisms that mediate downregulation of Kv1.3 expression during hypoxia are not fully understood. Moreover, no information is available whether adenosine has any effect on these important channels and through them regulates T cell function. We have obtained preliminary evidence that adenosine inhibits the activity of KCa3.1 channels. Therefore, in the current application we will test the hypothesis that the microenvironment of solid tumors, and specifically hypoxia and adenosine, inhibit Kv1.3 and KCa3.1 channels producing a multidirectional attack on T cells that weakens the immune defense. We will perform experiments to identify the mechanisms that mediate downregulation of Kv1.3 expression in hypoxia. Furthermore, we will study the signaling pathways and functional relevance of KCa3.1 inhibition during hypoxia. We will also engineer multivalent nanoparticles to selectively target the expression of molecules involved in the decrease immune function by adenosine. Findings from the proposed studies will provide new insights into the mechanisms involved in decrease immune surveillance in solid tumors. Furthermore they will provide novel therapeutic targets and approaches to maintain the ability of immune cells to fight cancer cells in the hypoxic microenvironment. PUBLIC HEALTH RELEVANCE: One of the functions of the immune system is to attack cancer cells and destroy them. Unfortunately, there are special conditions in tumors that inhibit immune cell ability to do this. We propose to study how the effects of those conditions on ion channels in the membrane of immune cells contribute to the failure of the immune system to destroy cancer cells.