Immunometabolic Programs Controlled by ER Stress in Cancer

项目摘要-由内质网应激控制的癌症免疫代谢计划 肿瘤创造了有害的微环境，阻碍了有效抗癌药物的开发和维持 豁免权。然而，在这种恶劣的环境中，肿瘤内免疫细胞如何整合和解释持续的应激信号 仍然没有完全定义。我们已经发现，恶性肿块中的不利条件破坏了 内质网(ER)在免疫细胞中的蛋白质折叠能力，引发调节失调 促进免疫抑制和恶性进展的“内质网应激”反应。因此，我们假设 了解和靶向肿瘤微环境中有害的内质网应激反应 这是开发新的、更有效的癌症免疫疗法的重大机遇。在一个 关键的最新进展，我们确定了内质网应激反应的IRE1a-XBP1s臂抑制了该基因的表达 Tagln2是一种未被充分研究的细胞骨架蛋白，与T细胞激活和效应器功能有关。我们发现 XBP1s缺陷的T细胞表现出增强的Tagln2表达，支持其保护功能 肿瘤部位。此外，我们建立了Tagln2协调维持强健T的主要代谢程序 细胞线粒体呼吸和效应器能力。这些新的发现促使我们剖析了 新的IRE1a-XBP1s-Tagln2轴控制肿瘤中T细胞代谢和功能的机制。 因此，这个项目的目标是i)了解内质网应激如何抑制Tagln2的表达，ii)建立 Tagln2使T细胞具有强大的代谢适应性，支持它们的抗肿瘤活性，以及iii)确定 Tagln2替代疗法增强实体瘤中嵌合抗原受体(CAR)-T细胞的活性。 我们推测，调节失调的内质网应激反应通过使Tagln2-2失活来阻碍肿瘤内T细胞的功能。 驱动生物能量计划，维持这种细胞骨架-线粒体轴可以用来改善 实体瘤过继T细胞免疫治疗的疗效观察我们将在以下背景下测试这一新的假设 免疫治疗--通过以下具体目标治疗难治性卵巢癌： 目的1.明确内质网应激反应抑制卵巢钙化T细胞Tagln2的机制。 目的2.确定Tagln2作为一种代谢驱动因子在抗肿瘤T细胞功能中的作用。 目的3.验证保留Tagln2活性可增强卵巢癌CAR-T细胞免疫治疗的假说。 总而言之，拟议的项目将扩大我们对肿瘤免疫调节机制的理解。 并承诺为新的干预措施铺平道路，以增强细胞的功效 针对实体恶性肿瘤的免疫治疗。

Project Summary – Immunometabolic Programs Controlled by ER Stress in Cancer Tumors create hostile microenvironments that impede the development and maintenance of effective anti-cancer immunity. Yet, how intratumoral immune cells integrate and interpret persistent stress signals in this harsh milieu remains incompletely defined. We have uncovered that adverse conditions within malignant masses disrupt the protein-folding capacity of the endoplasmic reticulum (ER) in infiltrating immune cells, triggering dysregulated “ER stress” responses that promote immunosuppression and malignant progression. Therefore, we postulate that understanding and targeting detrimental ER stress responses in the tumor microenvironment represents a major opportunity to develop new and more effective forms of cancer immunotherapy. In a key recent advance, we determined that the IRE1a-XBP1s arm of the ER stress response inhibits the expression of Tagln2, an understudied cytoskeletal protein implicated in T cell activation and effector function. We found that XBP1s-deficient T cells demonstrate enhanced Tagln2 expression that supports their protective function at tumor sites. Moreover, we established that Tagln2 coordinates major metabolic programs that sustain robust T cell mitochondrial respiration and effector capacity. These new findings have prompted us to dissect the mechanisms by which the novel IRE1a-XBP1s-Tagln2 axis controls T cell metabolism and function in cancer. Hence, the goals of this project are to i) understand how ER stress inhibits Tagln2 expression, ii) establish that Tagln2 equips T cells with robust metabolic fitness that supports their anti-tumor activity, and iii) determine that Tagln2 replacement therapy enhances the activity of chimeric antigen receptor (CAR)-T cells in solid tumors. We hypothesize that dysregulated ER stress responses hinder intratumoral T cell function by disabling Tagln2- driven bioenergetic programs, and that sustaining this cytoskeletal-mitochondrial axis could be used to improve the efficacy of adoptive T cell immunotherapy in solid tumors. We will test this novel hypothesis in the setting of immunotherapy-refractory ovarian cancer (OvCa) through the following Specific Aims: Aim 1. Define the mechanisms by which ER stress responses inhibit Tagln2 in OvCa-infiltrating T cells. Aim 2. Establish the role of Tagln2 as a metabolic driver of competent anti-tumor T cell function. Aim 3. Test the hypothesis that preserving Tagln2 activity enhances CAR-T cell immunotherapy in OvCa. Collectively, the proposed project will expand our mechanistic understanding of immune regulation in the tumor microenvironment and promises to pave the way for novel interventions that augment the efficacy of cellular immunotherapy against solid malignancies.