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. CD8+ tumor-infiltrating lymphocytes are associated with improved overall survival and have been described in several solid tumors, including 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 for ovarian cancer 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 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 HGSOC 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 alternation in immune related genes in ovarian cancer cells treated with rMFAP5. The results showed markedly higher CD47 expression in rMFAP5 treated cells than control cells. CD47 is an integral membrane protein, in both cancer cells and CD8+ T cells. It has been demonstrated to induce apoptosis in CD8+ T cells and trigger inhibitory signals on macrophages to prevent phagocytosis of cancer cells, thus disabling the possibility to activate CD8+ T-cells. We therefore hypothesize 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 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B045. doi:10.1158/1535-7163.TARG-19-B045

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.