Abstract P1-04-02: Improving immunotherapy response by epigenetic modulation

Abstract

Abstract The presence of predicted neo-antigens in any given tumor is highly correlated with total somatic mutational burden of the same tumor genome. However, many potential neo-antigens are never transcribed, translated, or presented as antigens, partially because they lie in regions of the genome that are transcriptionally-repressed by cytosine methylation of promoter-CpG islands. Treatment with DNA methyltransferase inhibitors (DNMTi) can hypothetically lead to re-expression of many potential neo-antigens. Furthermore, the presence of neo-antigens have been linked to immunotherapy outcomes in patients. Our hypothesis is that tumors with reduced mutational burden can be maximized for neo-antigen presentation by activating transcription and translation of these sequences through DNMTi treatment. Our preliminary results showed that the DNMTi guadecitabine (SGI-110), a second-generation hypomethylating agent, treatment decreases methyl-cytosine in genomic DNA both in vitro and in vivo. In addition, SGI-110 treatment enhances MHC-II expression on murine mammary carcinoma MMTV-Neu cells upon IFN-γ stimulation in vitro and increases T-cell infiltration in vivo. Currently, we are performing whole-exome-sequencing and RNA-sequencing to track somatic mutations from DNA to RNA. We will further track somatic mutations from RNA→ MHC-presented peptide sequences using MHC immunoprecipitation followed by mass spectroscopy analysis. In addition, we will explore the role of guadecitabine therapeutic priming on response to αPD-L1 immunotherapy. These studies will provide a pre-clinical data to evaluate the potential for combined epigenetic and immune-therapy in a clinical trial for breast cancer. Citation Format: Luo N, Estrada VM, Sanders ME, Balko JM. Improving immunotherapy response by epigenetic modulation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-02.