Abstract 4145: Stromal heterogeneity and immune response in ovarian cancer

Abstract

Abstract Ovarian cancer is the most lethal gynecologic malignancy in the US. Our group and others has shown that CD8+ lymphocyte infiltration in the ovarian tumor epithelium is associated with prolonged survival in patients with high-grade serous ovarian cancer (HGSOC). Despite the increasing evidence on stromal involvement in tumor progression, the underlying genetic composition of the stromal cells that could regulate the infiltration and activation of CD8+ cytotoxic T lymphocytes (CTLs) in ovarian cancer is not fully understood. How tumor heterogeneity contributes to a different in immune response remains a challenge question that needs to be addressed. The present study seeks to evaluate the roles and to delineate the underlying mechanisms by which stromal cancer associated fibroblasts (CAFs) modulates immune response in ovarian cancer, particularly immune suppression by CAF-derived protein factors. By laser microdissection of tumor tissue samples from HGSOC patients, we generated cell type specific expression profiles and identified a CAF-specific gene signature for ovarian cancer. Genes expressed exclusively by CAFs that are associated with differential immune response were identified by comparing CAF expression profiles from HGSOC patients with high and low tumor-infiltrated CD8+ T cell densities. Among the differentially expressed genes identified, immunostaining results showed a significant inverse correlation between stromal MFAP5 expression and intratumoral CD8+ T cell density in HGSOC tissue samples (p = 0.006). The results were further confirmed by correlating stromal MFAP5 protein expression and intratumoral CD8+ T cell density. Our recent studies showed that increased stromal MFAP5 expression is associated with poorer survival in HGSOC patients and MFAP5 modulates ovarian caner invasion and motility potential. Together with our preliminary data showing that MFAP5 modulates the expression of immune-related genes, we hypothesize that stromal MFAP5 may generate an immunosuppressive microenvironment through suppressing CD8+ T cell activation and trafficking in the ovarian tumor tissue. Cell culture experiment showed that recombinant MFAP5 protein treatment induced expression of CD47, an immune checkpoint protein, in cancer cells and downregulated CXCL13, a chemokine essential for immune cell adhesion, in endothelial cells. Using animal models, these findings were further validated. Based on our data, animal studies will be performed to further evaluate the efficacy of immune activation by targeting stromal MFAP5 in ovarian cancer treatment. Delineating the molecular mechanism by which MFAP5 modulates the immune responses in ovarian cancer will help to design novel treatment modalities based on stromal MFAP5 blockade, which will promote activation and trafficking of cytotoxic CD8+ T cells and improve patient survival rates. Citation Format: Tsz-Lun Yeung, Cecilia S. Leung, Kwong-Kwok Wong, Samuel C. Mok. Stromal heterogeneity and immune response in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4145.