Abstract B20: p53 regulation of repetitive elements and the interferon response in cancer
Authors: Arthofer Elisa , Diab Noor , Chiappinelli Katherine Bakshian 
Published: June 2021

Here we characterize the effects of p53 status on the immune microenvironment of tumors. Specifically, we focus on the immune response induced by treatment with epigenetic modulators like 5-azacytidine (Aza), a DNA methyltransferase inhibitor (DNMTi), and whether this differs in tumors with and without functional p53. We and others have previously shown that cancer cells elicit an immune response when treated with epigenetic modulators such as DNMTis. These drugs inhibit methylation-induced gene silencing and cause re-expression of repetitive elements. Furthermore, they trigger interferon signaling in tumors by upregulation of double-stranded RNA (dsRNA) including DNA methylated endogenous retroviruses (ERVs), remains of exogenous retroviruses that integrated into the germline millions of years ago. The tumor suppressor protein p53, which is mutated in over half of all cancers, acts as a transcriptional repressor of ERVs. Little is known about the interaction between ERVs and p53 in a pathophysiologic model such as cancer. We hypothesize that p53 mutations influence the epigenetic regulation and ERV-induced immune signaling in cancer cells treated with Aza. We injected mouse ovarian cancer cells with p53 wild-type or null status into a syngeneic animal model for ovarian cancer and treated these mice with vehicle or Aza, an FDA-approved epigenetic modulator for myelodysplastic syndrome. We report that after 15 weeks, mice injected with p53 null cells present with a significantly higher tumor burden reflected in occurrence and volume of abdominal ascites fluid, weight gain over time, and shorter survival compared to mice injected with p53 wild-type cells. Further, Aza treatment compared to mock has a significant positive effect on tumor burden and survival but exclusively in mice with p53 null cells. No significant differences between treatments in the groups containing p53 wild-type cells were observed, indicating that the presence of p53 in these tumor cells likely abrogates the immunologic antitumor effects of Aza. This makes sense as p53 is a major transcriptional regulator of repetitive elements such as ERVs, which are upregulated after Aza treatment in this tumor model. We are currently characterizing differences in immune regulation of these treatment groups, in particular, infiltrating lymphocytes and Type I interferon signaling, which is crucial for the antitumor effect of Aza. We have studied how functional or lack of p53 contributes to the epigenetic regulation of ERVs and their potential to sensitize patients to immune therapy. We are now creating isogenic ovarian cancer cells containing wild-type or null as well as p53 point mutations, which occur in the majority of cancers. In doing so, we will gain novel information about the effects of mutant p53 on the ERV-induced immune response in tumor cells. Considering the vast amount of cancers harboring p53 mutations, assessing the p53 mutational status in cancers could become a useful biomarker for epigenetic therapies activating ERVs.

Citation Format: Elisa Arthofer, Noor Diab, Katherine Bakshian Chiappinelli. p53 regulation of repetitive elements and the interferon response in cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B20.