Abstract 2232: A novel immune checkpoint regulator in the ovarian cancer microenvironment

Abstract

Abstract High-grade serous ovarian cancer (HGSC) is the most lethal gynecologic malignancy, accounting for 70-80% of ovarian cancer deaths worldwide. Despite promising results with platinum-based chemotherapy and cytoreductive surgery, more than 75% of women with HGSC will relapse after completion of first-line therapy. The window of opportunity to tailor therapeutic interventions to control progressive disease is limited due to the inherent tumor heterogeneity and genomic instability of HGSC and to how these factors contribute to different immune responses. Recent studies show that biomarkers expressed by specific stromal cell types in the tumor microenvironment may have prognostic value. Our group and others has shown that CD8+ lymphocyte infiltration in the ovarian tumor epithelium is associated with prolonged survival in patients with HGSC. Nevertheless, the molecular mechanisms underlying the promotion or inhibition of CD8+ lymphocyte infiltration by stromal cells in ovarian cancer are not fully understood.By laser microdissection and transcriptome profiling of tumor tissue samples from HGSC patients, we identified stromal cancer associated fibroblasts (CAF)-specific gene signatures that are associated with the survival of patients and with the differential tumor immune response. Among the differentially expressed genes identified, validation study by qPCR, Imaging CyTOF and immunohistochemistry indicated a significant inverse correlation between stromal MFAP5 expression and intratumoral granzyme B+/CD8+ T cell density in HGSC tissue samples. MFAP5 is an extracellular matrix glycoprotein and an important component in the assembly of microfibrils. Moreover our recent studies showed that increased stromal MFAP5 expression is associated with poorer survival in HGSC patients. This led to the hypothesis that MFAP5 could acts as an immune checkpoint mediator by generating an immunosuppressive environment through suppressing CD8+ T cell activation and trafficking in the ovarian tumor tissue. To test this hypothesis, transcriptome profile was performed to identify alteration in immune related genes in ovarian cancer cells treated with rMFAP5. The results showed markedly higher expression of CD47, a novel immune checkpoint molecule that triggers “don't eat me” signals on macrophages, in rMFAP5 treated ovarian cancer cells and CD8+ T cells than control cells. Additionally, we demonstrated that rMFAP5 induced apoptosis in CD8+ T cells and reduced macrophage phagocytosis potential. These data suggest that CD47 mediates the effect of MFAP5 on inducing apoptosis in CD8+ T-cells as wells as on preventing macrophage phagocytosis of ovarian cancer cells.Overall, the identification of MFAP5 as a novel stroma-derived immunomodulatory molecule that is associated with patient survival rates and CD8+ T cell densities presents a unique opportunity for the development of new treatment strategies that may improve survival. Citation Format: Sammy Ferri Borgogno, Tsz-Lun Yeung, Cecilia S. Leung, Chi Lam Au Yeung, Ying Zhu, Stephen T. Wong, Samuel C. Mok. A novel immune checkpoint regulator in the ovarian cancer microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2232.