Immunometabolic Programs Controlled by ER Stress in Cancer

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.