Unfolding anti-cancer immunity: New roles for ER stress sensors in the tumor microenvironment
Speaker: Juan Cubillos
Weill Cornell Medicine [New York, USA]
Host: Eugenio Santos
Salón de actos del Centro de Investigación del Cáncer
Harnessing the intrinsic ability of our immune system to eliminate malignant cells represents the most promising new anti-cancer strategy since the development of chemotherapy. While cancer immunotherapy has been designated a scientific breakthrough, tumor-induced immunosuppression still represents a major impediment to the success of this new approach. We recently found that ovarian cancer inhibits the development of protective anti-tumor immunity by inducing a state of continued “Endoplasmic Reticulum (ER) Stress” in tumor-associated dendritic cells (tDCs). Sustained activation of the IRE1-XBP1 arm of the ER stress response in DCs was necessary for the aggressive and accelerated progression of primary and metastatic ovarian cancers in various preclinical models of disease. Mechanistically, hyperactive XBP1 disrupted crucial metabolic pathways in tDCs and caused severe immune cell dysfunction at tumor sites. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective T cell-mediated anti-tumor immunity. Our findings uncover a new regulatory role for XBP1-driven signaling in DCs of the tumor microenvironment and suggest that targeting aberrant ER stress responses may represent a new strategy to control tumor-induced immunosuppression.