Abstract 5746: CRISPR9-mediated FGL2-KO in tumor cells impairs tumor progression in brain and triggers antitumor immune memory systematically via NF-κB dependent Batf3 expression in DCs

Abstract

Abstract Brain cancer is the 10th leading cause of death in United States with increasing primary tumor morbidity and secondary brain metastasis morbidity. Glioblastoma (GBM) is most lethal brain tumor with less than 5% 5 years survival rate marked by significant resistance to majority of therapies targeting tumor cells or tumor microenvironment. Here we shown one approach to convert aggressive GBM cells to immunogenic tumor cells by knockout FGL2 in GBM cells to evoke efficient anti-tumor immunosurvilliance. FGL2 is an immunosuppressive molecule and its expression level is strongly correlated with glioma grade and poor diagnosis. FGL2 from GBM cells, but not from host cells, is essential for immune evasion dependent GBM progression using both preclinical GBM and brain metastatic tumor models. Knockout FGL2 in GBM cells completely abolish tumor progression of GBM models challenged with low or high number of tumor cells in immunocompetent mice and protect mice from tumor rechallenge in periphery. This eradication effect is impaired in immune deficient mice and CD8+ T cells depleted mice, but not in FGL2KO mice, showing the necessarily of immune system to eliminate FGL2KO tumor cells and the requirement of FGL2 in tumor cells to evade immunosurvilliance. To understand how the systemic CD8+ T cell-dependent anti-tumor response and memory was induced by FGL2KO GBM cells, we studied the impact of FGL2KO tumor cells on dendritic cells (DCs) which control immune response via its critical role in the generation of effective cytotoxic T lymphocyte (CTL) responses. Knockout FGL2 in GBM cells induced CD8a+/CD103+ DCs accumulation in brain in vivo; DCs proliferation and CD103+ DCs induction in vitro. In agreement with this discovery, knockout Batf3, a key transcription factor regulating CD8a+/CD103+ DCs, reverse the impact of FGL2KO in GBM cell in vivo. By molecule analysis, a novel signaling pathway was revealed that knockout FGL2 in GBM cells induce NF-κ B activation, and this activation induced Batf3 and associated CD103 expression in DCs. Therefore, target specific molecule in GBM cells, such as knockout FGL2, can convert aggressive GBM cells to immunogenic cells, pointing to new approach for immune therapy. Citation Format: Jun Yan, Qingnan Zhao, Konrad Gabrusiewicz, Ling-Yuan Kong, Longfei Huo, Xueqing Xia, Jun Wei, Jingda Xu, Eric Davis, Amy B. Heimberger, Shulin Li. CRISPR9-mediated FGL2-KO in tumor cells impairs tumor progression in brain and triggers antitumor immune memory systematically via NF-κB dependent Batf3 expression in DCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5746.