Abstract A056: Incessant ER stress responses promote dendritic cell dysfunction in ovarian cancer

Abstract

Harnessing the intrinsic ability of our immune system to recognize and eliminate malignanT-cells represents the most promising anticancer strategy since the development of chemotherapy. However, hostile microenvironmental conditions within aggressive solid tumors inhibit the optimal activity of protective immune cells. Targeting immunosuppression and re-programming immune cell function in the tumor microenvironment are thus fundamental requirements for developing successful cancer immunotherapies. Our CRI postdoctoral project aims at identifying, understanding and disabling the molecular mechanisms by which endoplasmic reticulum (ER) stress responses inhibit the natural function of dendritic cells (DCs) in the ovarian cancer microenvironment. The central hypothesis of this study is that ovarian tumors trigger ER stress and aberrant activation of the IRE1-XBP1 pathway in infiltrating DCs to cripple key immuno-metabolic processes and impede the development of protective T-cell responses. To determine how IRE1α-XBP1 overactivation defines regulatory DC phenotypes in the ovarian cancer microenvironment, metastatic ovarian tumors were developed in ER stress-Activated Indicator (ERAI) reporter mice. We found that DCs demonstrating IRE1 activation in the tumor microenvironment overexpress tolerogenic and immunosuppressive molecules. Next, to determine whether tumor-derived factors may affect DC metabolism, we optimized an ex vivo culture system that recreates the tumor microenvironment using malignant ascites samples from ovarian cancer patients. We treated human monocyte-derived DCs from healthy donors with patient-derived ovarian cancer malignant ascites supernatants and assessed the bioenergetic profile of DCs. Oxygen consumption rate (OCR), which measures mitochondrial respiration, ATP production and spare respiratory capacity, was increased in DCs exposed to ascites supernatants. We found that these metabolic changes upon ascites treatment relied on IRE1a-XBP1 pathway. Further, since therapeutic DC-based vaccines have shown limited effects in ovarian cancer patients, we tested the novel translational hypothesis that XBP1-deficient bone marrow-derived DCs (BMDCs) would be better equipped to endure and function in the tumor microenvironment when used as therapeutic vaccines. While adoptive transfer of WT BMDCs did not induce any therapeutic effect, treatment with XBP1-deficient BMDCs elicited a marked increase in overall host survival. This result suggest that compared with WT BMDCs, their XBP1-deficient counterparts were resistant to the immunosuppressive effects of the tumor microenvironment. Our results provide a unique mechanistic rationale for targeting the IRE1-XBP1 arm of the ER stress response as a potent approach to reprogram and enhance antitumor immune cell function in cancer. These findings should also pave the way for devising a new generation of cancer immunotherapies that may improve the dismal survival of >21,000 American women affected by ovarian cancer each year. Citation Format: Chang-Suk Chae. Incessant ER stress responses promote dendritic cell dysfunction in ovarian cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A056.