Global Control of Ovarian Cancer Immunity by Aberrant ER Stress Responses
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. Every year, more than 21,000 patients are diagnosed with ovarian cancer and approximately 14,000 die because of this devastating disease. While basic knowledge on cancer cell biology has markedly increased over the last three decades, current treatments for metastatic carcinoma, the stage at which most ovarian cancers are diagnosed, lead to a 5-year survival rate of only 27%. 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 natural 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 in response to various immunotherapeutic agents. Interestingly, ovarian cancer patients with high accumulation of T cells inside the tumor survive longer than those with reduced numbers of intratumoral 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 poorly effective ovarian cancer treatments presently used in the clinic. Nevertheless, it is becoming increasingly clear that ovarian cancers have developed remarkable suppressive strategies to prevent and counteract the anti-tumor effects of diverse immune cell subsets. This proposal therefore aims at uncovering and characterizing new mechanisms through which ovarian tumors restrain the anti-cancer activity of immune cells. Juan Cubillos-Ruiz, the Early-Career Investigator (ECI) in this award, has devoted the last 10 years of his scientific career to studying the complex biology of ovarian cancer. His career goals in ovarian cancer research are to identify, understand, and disable the cellular and molecular processes used by ovarian tumors to usurp protective immune cell functions. In a key recent advance, the ECI established that immune cells within ovarian tumors are "stressed out" due to adverse environmental conditions within these malignant masses such as decreased oxygen availability and lack of nutrients. Therefore, the central hypothesis of this project is that stressed out immune cells in ovarian cancer hosts are unable to execute their crucial anti-tumoral functions. Accordingly, this 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. In addition, this proposal will test the novel translational hypothesis that inhibiting immune stress within the tumor environment could be used as a new strategy to restrain ovarian cancer progression. Successful accomplishment of the research plan described in this proposal will unveil new classes of fundamental mechanisms and novel therapeutic targets that will position the ECI as a leader in the field and that will promote an independent, unique, and sustained career in ovarian cancer research. More importantly, this proposal will provide the first 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. During the next 5 years, the ECI will also partner with medicinal chemists to g
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610438
Entities
People
- Juan R Cubillos-Ruiz
Organizations
- United States Army
- Weill Cornell Medicine