Enhancing Cancer Immunotherapy through Pharmacological Inhibition of ER Stress Sensors

ASPIRE Award (2018-Present)

Aggressive tumors have evolved strategies that enable them to thrive under adverse conditions. One such example is over-activation of the normal stress response of the endoplasmic reticulum (ER) in immune cells, which causes improper cellular function due to disorganized and incomplete protein production. However, it has not yet been confirmed whether activation of the ER stress response in infiltrating immune cells is fundamental to tumor survival. Dr. Juan Cubillos-Ruiz at Cornell University is working to address this question. He and his team have already determined that ovarian cancer does induce an ER stress response in T cells – specifically through activation of the IRE1-XBP1 pathway, which controls cellular metabolism and allows the initiation of cancer-protective mechanisms. In this project, the team is studying how abnormal ER stress responses may affect metabolism in mitochondria, which could, in turn, change the epigenetics and function of cancer-reactive T cells and hinder a patient’s response to immunotherapy. They are also probing whether blocking the IRE1-XBP1 signaling pathway could improve patient response to cancer treatment. The results of these efforts will enable the development of ER stress response-targeting drugs that could be combined with immunotherapies to improve outcomes in patients with immune evasive cancers.