Abstract PR2: Overexpression of MAVS stimulates antitumor immunity and significantly reduces tumor growth of immune-insensitive colorectal cancer in vivo

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). This is perhaps best exemplified in colorectal carcinomas (CRCs) where ~90% of CRCs (non-MSI) are unresponsive to ICBs. Secondary analyses of ICB responders suggest that the presence of T cells and a functional interferon signal transduction pathway within cancer cells is likely required for PDL1 ICB efficacy, as mutations in this pathway confer resistance to PD1/PDL1 therapies. Our studies have indicated that this lack of response may be due to mutations and loss of genes that mediate the innate immune responses in tumor cells, such as MAVS (Mitochondrial Antiviral Signaling Protein), which we found were significantly reduced in colorectal cancer. Thus, we hypothesize that stimulation of the MAVS pathway would elicit strong interferon signaling capable of reversing immunosuppression to allow for successful immune-mediated tumor regression. To circumvent issues associated with single ligand stimulation, we exploited the bow-tie structure of the MAVS through its overexpression as a novel genetic means to elicit ligand free innate immune signaling in the TME. We found that overexpression of MAVS elicited robust stimulation of Type I and II interferon pathways, along with a unique interferon gene signature (through transcriptomic analysis of infected primary cells), in comparison to TLR and STING stimulated counterparts. Using MAVS inducible-expressing colorectal cell lines, we found that MAVS expression stimulated significant antitumor responses in vivo through its stimulation of adaptive tumor-specific immune responses in anti-PDL1-resistant models. Moreover, in 20% (4 out of 20) of MAVS-induced cancers, we observed complete tumor regression as well as an immunologic memory response (in 100% of regressed mice) through tumor rechallenge experiment. Utilizing MAVS expressing viral (adeno and AAV) vectors, we could demonstrate significant induction of interferon responses among different cells in the tumor microenvironment, including tumor cells, fibroblasts, as well as dendritic cells. Intralesional injection of tumors using these vectors elicited profound antitumor responses against primary tumors, as well as an abscopal effect against syngeneic implanted tumors. However, we found that MAVS expression significantly upregulated PDL1 in infected cells, suggesting that MAVS vectors may synergize with PDL1 ICB. In conclusion, our data demonstrate the importance of innate immunity activation by MAVS pathway in generating antitumor effects and immune “hot spots” in colorectal tumor microenvironment, which may synergize with PD1/PDL1 checkpoint blockade antibodies. Thus, our findings suggest that a MAVS cancer gene therapy may offer an alternative approach to activate immunity in “immunologically cold” or “T-cell excluded” tumors. This abstract is also being presented as Poster A45. Citation Format: Bin-Jin Hwang, Li-Chung Tsao, Gabriel DeLeon, Junping Wei, Xiao-Yi Yang, Gangjun Lei, Tao Wang, Michael M. Morse, Herbert Kim Lyerly, Zachary Conrad Hartman. Overexpression of MAVS stimulates antitumor immunity and significantly reduces tumor growth of immune-insensitive colorectal cancer in vivo [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR2.