Abstract PO002: APOBEC mutagenesis as a driver of tumor evolution by promoting tumor recurrence and modulating tumor-immune system interactions in a syngeneic murine model of breast cancer

APOBEC-mediated mutagenesis is one of the most common endogenous sources of mutations in human cancer. APOBEC mutations are due to the episodic activity of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of cytidine deaminases, which catalyze the deamination of cytosine to uracil on single-stranded DNA. Cytidine deamination can be repaired to result in C-to-T and C-to-G mutations throughout the somatic genome. APOBEC mutational signatures have been identified in 22 different tumor types and are particularly enriched in bladder, head and neck, cervical, and breast cancer. Importantly, APOBEC mutagenesis is the main source of hypermutation in most breast tumors. Ongoing APOBEC mutational processes introduce genetic heterogeneity in populations of cells, although the in vivo functional consequences of these mutations on neoantigen formation, immunogenicity, and tumor evolution are unknown. Here, we designed syngeneic murine mammary tumor models to induce APOBEC mutagenesis in vivo and study how APOBEC mutational signatures shape tumor cell-intrinsic evolution and interactions with the tumor-immune microenvironment. In one murine model of HER2-driven mammary tumors, APOBEC mutagenesis significantly accelerates tumor recurrence following HER2 inhibition. However, we also found that in an immunocompetent mouse model of HER2-driven primary tumors, ongoing APOBEC mutagenesis slows tumor growth and triggers an antitumor adaptive immune response. The immune response consists of increased infiltration of CD4+ and CD8+ T cells and CD103+ dendritic cells, reduced infiltration of immunosuppressive Tregs and macrophages, and upregulated proinflammatory cytokines and PD-1/PD-L1 expression. Using a catalytically inactive mutant of the APOBEC enzyme, we discovered that the tumor growth defect requires the mutagenic activity of the APOBEC enzyme. Further, the growth defect of APOBEC tumors is largely abolished in immunodeficient NOD-scid-gamma mice, suggesting that the effects on tumor growth are mediated by the immune response. Interestingly, depletion of CD4+ and CD8+ T cells does not rescue the growth defect of the APOBEC tumors, despite the robust T cell response following APOBEC mutagenesis. These data suggest that APOBEC mutagenesis has protumor and antitumor roles in shaping tumor evolution by promoting tumor recurrence and stimulating an antitumor immune response, independent of T cell-mediated cytotoxicity, and may reveal immunotherapeutic treatment strategies for breast cancer patients with APOBEC mutational signatures. Citation Format: Ashley V. DiMarco, Xiaodi Qin, Brock McKinney, Ryan Lupo, Jichun Xie, Kouros Owzar, James Alvarez. APOBEC mutagenesis as a driver of tumor evolution by promoting tumor recurrence and modulating tumor-immune system interactions in a syngeneic murine model of breast cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO002.