1. Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer.
- Author
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Moufarrij S, Srivastava A, Gomez S, Hadley M, Palmer E, Austin PT, Chisholm S, Diab N, Roche K, Yu A, Li J, Zhu W, Lopez-Acevedo M, Villagra A, and Chiappinelli KB
- Subjects
- Animals, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, DNA (Cytosine-5-)-Methyltransferases metabolism, Drug Resistance, Neoplasm drug effects, Enzyme Inhibitors therapeutic use, Female, Histone Deacetylase 6 metabolism, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors therapeutic use, Humans, Interferon-gamma metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells cytology, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism, Ovarian Neoplasms drug therapy, Ovarian Neoplasms immunology, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Survival Rate, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, Enzyme Inhibitors pharmacology, Histone Deacetylase 6 antagonists & inhibitors, Signal Transduction drug effects, Tumor Microenvironment drug effects
- 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-1
hi 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.- Published
- 2020
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