A sUPR Driver of T-Cell Metabolic Dysfunction in Ovarian Cancer
Abstract
Ovarian carcinoma is the most lethal cancer of the female reproductive tract and is the fifth leading cause of cancer-related death in American women. While basic knowledge on cancer cell biology has markedly increased over the last decades, current treatments for metastatic carcinoma, the stage at which most ovarian cancers are diagnosed, lead to a 5-year survival rate of less than 30%. These classical treatments based on surgery and chemotherapy seek to eliminate tumors that are initially sensitive to drugs. However, the usual failure of this approach to eradicate all malignant cells promotes the development of drug resistance cancer and aggressive systemic relapse. Therefore, novel and more effective approaches are urgently needed in the clinic to complement the standard treatments and improve the dismal prognosis of ovarian cancer patients. Specific cells in our immune system, called T cells, exhibit a remarkable ability to recognize and kill cancer cells. Harnessing their capacity to fight tumors represents the most promising anti-cancer strategy since the development of chemotherapy, as evidenced by the dramatic shrinkage of human melanoma and lung cancer in response to various immunotherapeutic agents. Notably, ovarian cancer patients with high accumulation of T cells inside the tumor survive longer than those with reduced numbers of intra-tumoral T cells. These observations indicate that the immune system can exert pressure against ovarian cancer progression and suggest that therapies capable of unleashing anti-tumor T cells could offer a strategy to support the standard treatments. Nevertheless, ovarian cancers develop potent mechanisms to prevent and counteract the anti-tumor effects of immune T cells. Our Investigator Initiated Research Project seeks to uncover and characterize the dominant mechanisms through which ovarian tumors restrain the anti-cancer activity of our immune system. Supported by our initial Ovarian Cancer Academy - Early-Career Investigator Award of the Department of Defense, our group discovered that immune cells within ovarian tumors are stressed out due to the adverse environmental conditions that these malignant masses create, such as decreased oxygen availability and lack of nutrients. These harsh conditions, and the ensuing cellular stress provoked, render the immune system inactive and unable to spot and kill the cancer cells. Therefore, we postulate that identifying, understanding, and disabling the sensors of stress in immune T cells could be exploited as a novel approach to unleash protective and durable immune responses against ovarian cancer. Hence, our project will comprehensively characterize the tactics that ovarian cancers utilize to induce cellular stress in the immune system and will unveil the functional processes that are affected in stressed out immune cells. Moreover, our project will test the novel translational hypothesis that overcoming immune stress within the tumor environment could be used as a new strategy to restrain ovarian cancer progression. Therefore, our project is intimately connected with the following areas of emphasis relevance: understand the basic biology and etiology of ovarian cancer initiation, progression, metastasis, recurrence, genetics, and other critical events, as well as develop novel therapeutic strategies for ovarian cancer treatment. Successful completion of this project will unveil new classes of fundamental mechanisms and novel therapeutic targets for ovarian cancer. As such, this project is expected to provide a strong mechanistic rationale for targeting cellular stress pathways in the clinic as a novel approach to unleash protective immunity against, and prevent recurrence of, ovarian cancer. Since multiple pharmaceutical companies are currently developing drugs to target cellular stress pathways in other indications, our findings could have rapid clinical applicability towards eliminating ovarian cancer, thu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310204
Entities
People
- Juan R Cubillos-Ruiz
Organizations
- United States Army
- Weill Cornell Medicine