Abstract B66: Targeted activation of innate immune adaptors MAVS and STING promotes antitumor responses in colorectal cancer models (2018)

Abstract While the use of immune checkpoint blockade (ICB) has gained significant traction as a viable therapy for certain cancers, many more cancers remain refractory to immunotherapies due to their highly immunosuppressive microenvironment. This is perhaps best exemplified in the largest group of cancers, colorectal carcinomas (CRCs) where ~90% of CRCs (non-microsatellite instable) are unresponsive to ICBs. Recent studies have indicated that this lack of response may be due to mutations and loss of genes that mediate the innate immune responses, such as MAVS (Mitochondrial Antiviral Signaling Protein) and STING (Stimulator of Interferon Genes). We hypothesized that delivery of active versions of these genes would elicit strong interferon signaling that could reverse the tumor immunosuppressive environment, to effectively create immune “hotspots” and allow for successful immune-mediated tumor regression. As a proof-of-concept, we developed doxycycline-inducible activated forms STING and MAVS in mouse CRC models (MC38 and CT26 lines), and found the expression of MAVS or STING resulted in robust activation of interferon-stimulated genes and other cytokines/chemokines. To determine if delivery of these genes could be achieved in vivo, we developed cell lines capable of resisting the anti-viral effect of interferon stimulation. This system allowed us to generate adenoviral vectors that express active forms of MAVS and more recently, STING. We found that Ad-MAVS strongly elicited interferon signaling in a variety of cell types and tumor lines, suggesting its effectiveness as an interferon stimulatory agent. To determine its anti-tumor effect, we intra-lesionally injected tumors and observed strongly inhibited tumor growth and enhanced T-cell infiltration in established tumor masses in vivo. This correlated with enhanced anti-tumor specific T cell responses, but not humoral responses. The induction of local and systemic immunity was confirmed in a bi-lateral treatment model that demonstrated the impact of systemic immunity by MAVS induction. Furthermore, we found that MAVS-induced tumor regression was lost in NOD/SCID mice, suggesting that the induction of tumor-specific T-cell adaptive immunity was critical to anti-tumor responses. Lastly, we found the activation of MAVS resulted in upregulated expression of PD-L1 on tumor cells, suggesting combinatorial treatments of checkpoint blockades therapy with targeted MAVS activation can result in synergistic effects. In conclusion, our data demonstrated the importance of innate immunity activation by MAVS or STING pathway in generating immune hotspots in colorectal tumor microenvironment, which promotes antitumor adaptive T cell responses and tumor growth regression. Citation Format: Li-Chung Tsao, Herbert Kim Lyerly, Zachary Hartman, Gabriel Deleon. Targeted activation of innate immune adaptors MAVS and STING promotes antitumor responses in colorectal cancer models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B66.