While T cell-based therapies represent a novel approach to complement current treatments for metastatic ovarian cancer, tumor-induced immunosuppression restrains the optimal activity of cancer-reactive T cells. Thus, unveiling and targeting the pathways that tumors exploit in T cells to control their function is crucial for developing successful ovarian cancer immunotherapies.
The Endoplasmic Reticulum (ER) functions to process newly synthesized secretory and transmembrane proteins. Abnormal accumulation of unfolded proteins in this organelle causes “ER stress”, which is a hallmark feature of secretory cells and several diseases. Adaptation to protein-folding stress is mediated by the activation of an integrated signal transduction pathway known as the ER stress response. XBP1, a potent multitasking transcription factor governing this pathway, has been shown to promote malignant progression by supporting tumor cell survival under hypoxic conditions. Nevertheless, a role for XBP1 as key inhibitor of T cell-mediated anti-tumor immunity has not been identified.
Our preliminary findings indicate that aberrant XBP1 activation in T cells fosters ovarian cancer progression. Further, our preliminary data suggest that targeting T cell-derived XBP1 could enhance the quality of anti-tumor T cells that will be used in cancer immunotherapies. Hence, this project focuses on understating how ovarian cancer co-opts XBP1 function in T cells to inhibit anti-tumor immune responses. This knowledge will provide new insights into the immunobiology of ovarian cancer and will uncover new immune therapeutic targets in the tumor microenvironment. Dissecting the function of XBP1 as a negative regulator of anti-tumor immunity should pave the way for devising the next generation of effective immune-based treatments against ovarian cancer.
This grant is made possible in part through a generous donation from Tell Every Amazing Lady About Ovarian Cancer, the Louisa McGregor Ovarian Cancer Foundation.
Juan R. Cubillos-Ruiz, Ph.D. is a postdoctoral associate in the Department of Medicine at Weill Cornell Medical College in New York City. Juan obtained his Bachelor of Science degree in Microbiology at Universidad de los Andes (Bogota, Colombia) and completed his Ph.D. in Immunology at Dartmouth Medical School (Hanover, NH, USA) under the mentorship of tumor immunologist Dr. Jose Conejo-Garcia. His Ph.D. research focused on understanding and targeting the immune microenvironment of ovarian cancer. He pioneered the use of RNAi-loaded nanoparticles to re-program dendritic cell function in the tumor microenvironment and received the “John H. Copenhaver, Jr. and William H. Thomas, MD 1952” Predoctoral Fellowship Award for his basic and translational discoveries. Juan’s current research in the laboratory of world-renowned immunologist Dr. Laurie H. Glimcher focuses on understanding how the Endoplasmic Reticulum Stress Response regulates anti-tumor immune responses. Juan has been recipient of research awards from the Bill and Melinda Gates Foundation, the Cancer Research Institute and the Ragon Institute of MGH, MIT and Harvard. His overarching goal is to devise the next generation of targeted immunotherapies and make a decisive difference in the dismal prognosis of the more than 22,000 American women diagnosed every year with ovarian cancer.