Therapies that activate the host immune system have shown tremendous promise for a variety of solid tumors. However, in most cancer types, fewer than half of patients respond to these immunotherapies. Ovarian and breast tumors are often characterized by an immune suppressive microenvironment and response of these cancers to immune therapies has thus far been disappointing. Studies by our group and others have shown that DNA methyltransferase inhibitors (DNMTIs) can upregulate a wide range of genes involved in immune signaling in breast and ovarian cancer cells. The mechanism regulating this immune signaling in tumor cells involves DNMTIs and the demethylation and re-expression of endogenous retroviruses which can induce a cytosolic sensing double stranded RNA (dsRNA) anti-viral pathway resulting in Type I interferon signaling and the upregulation of interferon stimulated genes and immune cell attracting chemokines/cytokines. Furthermore, epigenetic changes, specifically de novo methylation, have been shown to play an important role in the promotion of CD8+ T cell exhaustion, which is a barrier to immune cell activation during checkpoint inhibition therapy. We propose that epigenetic therapy can modulate the tumor microenvironment via type 1 interferon signaling and can sensitize tumors to immune checkpoint therapy.
To test whether epigenetic treatment alters the tumor microenvironment to reduce immunosuppression, our analysis employed two immunocompetent murine cancer models. The first consists of C57Bl/6 mice transplanted with syngeneic ID8 ovarian surface epithelial cells. In this model, hemorrhagic ascites is a measure of tumor burden and the source of tumor and immune cells for analysis. In the second model, BALB/c mice were orthotopically transplanted with luminal-like, p53 null breast tumors, 2208L. We find, in both cancer models that clinically relevant doses of (DNMTi) and histone deacetylase (HDACi) inhibitors reduce tumor burden and improve overall survival. We show in the ovarian model that type I interferon signaling is necessary for AZA induced increases in the numbers of CD45+ immune cells and the percentage of active CD8+ T and NK cells in the tumor microenvironment. Antibody blockade of interferon alpha and beta receptor subunit 1 prevents reductions in tumor burden and increases in survival. In both the ovary and breast cancer models, AZA reduces the percentage of macrophages and myeloid derived suppressor cells in the tumor microenvironment. In breast, numbers of M-MDSCs are reduced while the G-MDSC population remains unchanged. Additionally, in contrast to the ovarian cancer model, CD45+ immune cells do not appear to be increased, but %CD3 cells are decreased by all treatments. In the ovarian model, addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and natural killer cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of the DNMTi/HDACi plus the immune checkpoint inhibitor alpha-PD-1 provides the best anti-tumor effect and longest overall survival, and may be an attractive concept for future clinical trials.
Citation Format: Zahnow CA. Epigenetic therapy activates type 1 interferon signaling to reduce immunosuppression and tumor burden [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr BS1-1.