Abstract 3667: Promotion of immunogenicity using epigenetic modulation and immune checkpoint inhibition in mouse models of breast cancer
Authors: Torres Evanthia T. Roussos , Ma Hayley , Christmas Brian , Armstrong Todd , Jaffee Elizabeth M. 
Published: July 2017

Checkpoint inhibition is a very successful treatment strategy in cancers that are naturally immunogenic by attracting T cells into the tumor microenvironment (TME) and promoting cytotoxic signaling pathways. While this strategy has shown some efficacy in metastatic breast cancer, most breast cancers are not highly immunogenic likely due to an immunosuppressive microenvironment and a lack of tumor antigen expression and recognition. One strategy to transform the breast TME into one that is immune responsive, is to use epigenetic modulation to expose tumor antigens, promote cytokine production, thus, attracting inflammatory cells into the tumor. Epigenetic modulation also has the potential to affect activation and trafficking of myeloid derived suppressor cells (MDSCs), known to alter the immunogenicity of the TME and thus, sensitizing tumors to checkpoint modulation. We hypothesize that combinatorial therapy primes the TME by increasing immunogenicity via alteration of T cells and MDSCs. We also hypothesize that combination therapy will significantly affect immune modulatory pathways. Alterations in these could serve as a functional read out of combinatorial therapy. We are using a Her-2/neu (neu-N) transgenic mouse model which through the use of various syngeneic cell lines has the capability to inform the response of Her2 and triple negative subtypes of breast cancer to immunotherapy. This model enables us to study the efficacy of different combinations of an epigenetic agent, the histone deacetylase inhibitor entinostat, and checkpoint inhibitors anti -programmed cell death protein (PD1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies, on tumor growth and metastatic progression, and to help identify co-stimulatory and inhibitory factors regulating T cell and MDSC responses. Characterization of tumor infiltrating lymphocytes and their functional capabilities are being investigated in primary tumors and metastases using fluorescence-activated cell sorting and immunohistochemistry. Thus far, there is a significant improvement in survival and delay in tumor growth in mice inoculated with neu expressing tumor cells treated with combination anti-PD1, anti-CTLA4 and entinostat as well as with anti-PD1 in combination with Entinostat. Preliminary results also suggest that epigenetic modulation with entinostat in combination with checkpoint inhibition improves the immune response within these tumors as evidenced by increased CD8+/T-regulatory cell infiltration, and increased monocytic-MDSCs into the TME. There are ongoing survival studies testing this combination therapy in mice inoculated with triple negative breast tumor cells. Future studies will further delineate the mechanisms by which epigenetic therapy alters the function of the inflammatory response to immunotherapy.

Citation Format: Evanthia T. Roussos Torres, Hayley Ma, Brian Christmas, Todd Armstrong, Elizabeth M. Jaffee. Promotion of immunogenicity using epigenetic modulation and immune checkpoint inhibition in mouse models of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3667. doi:10.1158/1538-7445.AM2017-3667