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Abstract
Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53−/− ovarian cancer with HDAC6i/DNMTi led to an increase in tumor-killing cells such as IFNg+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment.
Highlights
Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy
We demonstrate that combining the epigenetic modifiers HDAC6i (NextA) and DNMTi (Aza) upregulates the immune response in ovarian cancer in both in vivo and in vitro models
We found that the combination of Nexturastat A (NextA) with Aza upregulates the type I interferon response significantly more than either treatment alone
Summary
Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. Combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment. The tumor microenvironment (TME) is composed of both pro- and anti- cancer immune cells These include CD8 effector T cells that recognize specific antigens on tumor cells to kill them, natural killer (NK) cells, part of the innate immune system that can kill tumor cells, and immuno-suppressive cell types including macrophages, regulatory T cells, and myeloid-derived suppressor cells. We10–14 and others[15,16,17,18] have shown that DNMTis upregulate immune signaling, including the interferon response, tumor-associated antigens (TAAs), and antigen presentation, in ovarian cancer and other solid tumors. Inhibiting HDACs reduces tumor proliferation and several pan-HDAC inhibitors are approved for the treatment of T cell lymphomas[33]
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