Abstract LB-214: The immunosuppressive roles of ovarian stromal tumor microenvironment

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. Despite the increasing evidence on stromal involvement in tumor progression, the interactions between stromal fibroblasts and cancer cells, as well as the underlying genetic composition of the stromal cells that could regulate the infiltration and activation of CD8⁺ cytotoxic T lymphocytes (CTLs) and affect patient survival is not fully understood. 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 and transcriptome profiling of tumor tissue samples from ovarian cancer patients, we identified CAF-specific gene signatures for ovarian cancer that are associated with the survival duration of patients and with the differential tumor immune response. Among the differentially expressed genes identified, validation study by qPCR and immunohistochemistry indicated that stromal MFAP5 expression is significantly higher in patients with short survival duration and in patients with lower intratumoral CD8⁺ T cell density. Survival analysis result suggested that high stromal MFAP5 expression indicates poor disease prognosis (Hazard ratio=2.722, P<0.001, N=102) and multiplex immunofluorescent staining result suggested that high stromal MFAP5 expression is associated with lower density of CD8⁺ / Granzyme B⁺ activated tumor-infiltrating CTLs (P=0.006). Our in vitro data suggested that stromal MFAP5 promotes ovarian cancer cell invasion, migration and chemoresistance. At the same, we showed that MFAP5 modulates the expression of immune-related genes and generate an immunosuppressive microenvironment through suppression of CD8⁺ T cell activation in the ovarian tumor tissue. Cell culture experiment results showed that MFAP5 protein treatment induced upregulation of CD47, an immune suppressive protein, in cancer cells and CD8⁺ T cells. Using an ovarian cancer-bearing immune competent animal model, we demonstrated that inhibition of stromal MFAP5-mediated signaling cascade suppressed tumor progression and promoted tumor immune response.

Delineating the molecular mechanism by which MFAP5 modulates the progression and immune responses of ovarian cancer will shed light on the design of novel treatment modalities based on the blockade of tumor stroma-derived factors, which could 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, Michael J. Birrer, Stephen T. Wong, Karen H. Lu, Samuel C. Mok. The immunosuppressive roles of ovarian stromal tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-214. doi:10.1158/1538-7445.AM2017-LB-214