Abstract 1789: Triggering anti-tumor immunity by overexpressing of MAVS in combination with PD-L1 ICB in immune insensitive colorectal cancers

Abstract

Abstract While the use of immune checkpoint blockade (ICB) has gained significant traction as a viable therapy for cancers, many more cancers remain refractory to these immunotherapies due to their highly immunosuppressive tumor microenvironment (TME). From both the earlier published report and our analysis of clinical cohorts of colorectal cancer, we found that the expression of MAVS (Mitochondrial Antiviral Signaling Protein) was significantly reduced. Because MAVS are known to play a key role in the initiation of anti-viral innate immunity, we hypothesized that MAVS may be critical in anti-tumor immune response and tumor cells are under evolutionary pressure to reduce MAVS expression. As such, the stimulation of the MAVS pathway in tumor cells may be a necessary precursor to trigger anti-tumor immune response and reverse local immunosuppressive TME. To circumvent issues associated with intracellular double stranded RNA ligand stimulation, we exploited the ability of MAVS to constitutively polymerize and elicit broad downstream interferon signaling through an overexpression strategy. This approach provided a novel genetic mean to elicit ligand free innate immune signaling in the TME, which we found to elicit robust stimulation of multiple interferon genes. Overexpression of MAVS in colorectal cell lines stimulated significant anti-tumors responses in vivo, which we found to be primarily mediated through the induction of tumor antigen-specific adaptive immunity. Utilizing viral vectors overexpressing MAVS, we demonstrate significant induction of interferon responses among different types of tumor cells and different types of cells in the tumor microenvironment. Intra-lesional injection of tumors using these vectors elicited profound anti-tumor responses against primary tumors, as well as, an abscopal effect against syngeneic implanted tumors. Overexpression of MAVS also stimulated the expression of PD-L1 as an immunosuppressive feedback mechanism due to stimulation of the MAVS pathway. As such, we tested the combination of MAVS overexpression and PD-L1 ICB in colorectal cancers and found that this combination allowed for significantly improved anti-tumor immunity. In conclusion, our findings suggest that a combination of MAVS cancer gene therapy and ICB may offer an alternative approach to activate immunity in "immunologically cold" tumors. Citation Format: Bin-Jin Hwang. Triggering anti-tumor immunity by overexpressing of MAVS in combination with PD-L1 ICB in immune insensitive colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1789.