Immunometabolic Programs Controlled by ER Stress in Cancer

项目摘要-癌症中由ER应激控制的免疫代谢程序 肿瘤创造了不利的微环境，阻碍了有效抗癌药物的发展和维持。 免疫力然而，肿瘤内免疫细胞如何整合和解释这种恶劣环境中持续的应激信号， 仍然没有完全定义。我们已经发现，恶性肿块内的不利条件会破坏肿瘤的生长。 内质网（ER）在浸润性免疫细胞中的蛋白折叠能力，触发调节失调 促进免疫抑制和恶性进展的“ER应激”反应。因此，我们假设 了解和靶向肿瘤微环境中有害的ER应激反应， 代表了开发新的、更有效的癌症免疫疗法形式的重大机会。中 最近的一个关键进展，我们确定ER应激反应的IRE 1a-XBP 1 s臂抑制了 Tagln 2是一种研究不足的细胞骨架蛋白，与T细胞活化和效应功能有关。我们发现 XBP 1 s缺陷型T细胞表现出增强的Tagln 2表达，这支持了它们的保护功能， 肿瘤部位。此外，我们确定Tagln 2协调维持强大T细胞的主要代谢程序， 细胞线粒体呼吸和效应器容量。这些新发现促使我们剖析了 新的IRE 1a-XBP 1 s-Tagln 2轴控制癌症中T细胞代谢和功能的机制。 因此，本项目的目标是i）了解ER应激如何抑制Tagln 2表达，ii）建立 Tagln 2使T细胞具有支持其抗肿瘤活性的稳健代谢适应性，和iii）确定 Tagln 2替代疗法增强实体瘤中嵌合抗原受体（CAR）-T细胞的活性。 我们假设失调的内质网应激反应通过使Tagln 2失活而阻碍肿瘤内T细胞功能。 驱动的生物能量计划，维持这种细胞质-线粒体轴可以用来改善 过继性T细胞免疫疗法在实体瘤中的功效。我们将在以下环境中测试这一新的假设： 免疫治疗难治性卵巢癌（OvCa）通过以下具体目标： 目标1.定义ER应激反应抑制OvCa浸润T细胞中的Tagln 2的机制。 目标2.确立Tagln 2作为活性抗肿瘤T细胞功能的代谢驱动因子的作用。 目标3.测试保留Tagln 2活性增强OvCa中CAR-T细胞免疫疗法的假设。 总的来说，该项目将扩大我们对肿瘤免疫调节机制的理解， 微环境，并有望为新的干预措施铺平道路，增加细胞的功效。 针对实体恶性肿瘤的免疫疗法。

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.