PROJECT SUMMARY/ABSTRACT: Ovarian Carcinomas (OvCa) are the most life-threatening gynecological malignancy in the United States, claiming the lives of 14,000 women every year. The 5-year survival rate for metastatic OvCa is 27%, and standard treatments and therapies such as chemotherapy and surgical intervention are largely ineffectual, and can often promote drug resistance and recurrence of the cancer. The recent advent of cancer immunotherapy has proven effective in treating other cancers, but shown minimal efficacy in OvCa. Understanding the mechanisms that enable OvCa to escape immune control is crtical to developing more effective treatments. Ovarian Tumors have evolved strategies that enable them to thrive under adverse conditions while suppressing the protective function of immune cells. Recent studies demonstrate that these cancers provoke severe metabolic stress in myeloid cells to escape immune control, but it remains unknown how myeloid cells integrate and interpret metabolic stress signals in the tumor milieu. Our group determined that adverse conditions in the tumor microenvironment disrupt the protein-folding capacity of the endoplasmic reticulum (ER) in infiltrating immune cells. This process causes “ER stress” and elicits persistent responses via the IRE1α-XBP1 pathway, that alter key immunometabolic processes required for the initiation and maintenance of anti-tumor immunity. Multiple studies have shown that myeloid derived suppressor cells (MDSCs) and neutrophils can regulate anti-tumor T cell functions by depleting key amino acids from the TME. Our preliminary findings indicate that IRE1α-XBP1 signaling is required to sustain the capacity of MDSCs to express Arginase 1 (Arg1) and suppress T cell proliferation, by an unknown mechanism. The main goal of this proposal is to identify and understand the transcriptional and functional consequences of ER stress in tumor associated myeloid cells. Therefore, our central hypothesis is that maladaptive activation of ER stress sensors regulates the function of myeloid cell subsets in the tumor by altering their transcriptional programming to induce immunosuppressive phenotypes. Specifically, we postulate that the IRE1α-activated XBP1 transcription factor is a direct transcriptional inducer of Arg1. We also hypothesize that ER stress-driven gene signatures will delineate new transcriptional programs controlled by IRE1α-XBP1 in tumor associated neutrophils. Lastly, we will define how IRE1α-XBP1 ablation in tumor associated neutrophils modulates the cytotoxic activity of T cells and the development of protective anti-tumor immunity. Understanding the consequences of ER stress in tumor associated myeloid cells will be crucial to comprehensively define T cell dysfunction in ovarian cancer, and to develop new therapeutic interventions that augment T cell effector capacity in a harsh tumor microenvironment. The proposed project is mechanistically and translationally relevant as it has the potenti...