Abstract PR07: Developing syngeneic NOD tumor models to profile immunotoxicity and antitumor immunity in response to cancer immunotherapies in autoimmune-prone mice
With increasing use of cancer immunotherapies, it is evident that some patients develop immunotoxicity, termed immune-related adverse events (irAEs). Many of these irAEs are a consequence of a peripheral breakdown in self-tolerance but the basis, be it genetic, epitope spreading or environment, remains unclear. This highlights an urgent need to develop preclinical models to profile autoimmunity together with antitumor immunity to accurately assess the etiology by which autoimmune pathologies are induced in immunotherapy-treated cancer patients. We generated transplantable syngeneic tumor cell lines in the autoimmune-prone NOD background from spontaneous tumors and methylcholanthrene (MCA)-induced fibrosarcomas. We investigated whether the presence of tumor and level of tumor immunogenicity altered the severity and frequency of autoimmunity in response to cancer immunotherapies. Notably, individual and combination immunotherapies displayed distinct autoimmune pathologies, with induction of certain treatment-associated immunotoxicities, such as type 1 diabetes (T1D), associated with improved tumor control. Following, we investigated genetic and therapeutic strategies to abrogate immunotherapy-induced autoimmunity without impeding antitumor immunity. Multiple loci that control genetic susceptibility to autoimmunity in NOD mice have been identified including a major histocompatibility complex, as well as insulin-dependent diabetes (Idd) susceptibility loci localized to relevant immune checkpoints. Using NOD mice, congenic for individual IDD loci, we determined that NOR- or C57BL/6-derived gene loci provided significant protection from anti-PD-1/PD-L1-induced type 1 diabetes. In some cases, immune tolerance towards autoimmunity limited cancer immune surveillance; however, NOD mice congenic for NOR-Idd9 displayed both superior tumor control and significantly reduced incidence of T1D in comparison to NOD mice. This result suggests that in fact by abrogating the pathogenic autoimmune response, it is possible for improved tumor control to be afforded, representing an exciting area for mechanistic exploration. Together, these preclinical models provide a platform to assess safety profiles for cancer immunotherapies, identifying cellular mechanisms and therapeutic interventions that inhibit the development of autoimmunity while preserving antitumor immunity. Citation Format: Arabella Young, Vinh Nguyen, Jee Hye Kang, Sadaf Mehdizadeh, Amy Mei, Kathleen C. F. Sheehan, David V. Serreze, Yi-Guang Chen, Robert D. Schreiber, Jeffrey A. Bluestone. Developing syngeneic NOD tumor models to profile immunotoxicity and antitumor immunity in response to cancer immunotherapies in autoimmune-prone mice [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR07.