Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer
Journal
Scientific Reports
Journal Volume
10
Journal Issue
1
Date Issued
2020
Author(s)
Moufarrij S
Srivastava A
Gomez S
Hadley M
Palmer E
Austin P.T
Chisholm S
Roche K
Li J
Zhu W
Lopez-Acevedo M
Villagra A
Chiappinelli K.B.
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. © 2020, The Author(s).
SDGs
Other Subjects
Cd274 protein, mouse; DNA (cytosine 5) methyltransferase; enzyme inhibitor; gamma interferon; histone deacetylase 6; histone deacetylase inhibitor; programmed death 1 ligand 1; animal; C57BL mouse; CD4+ T lymphocyte; CD8+ T lymphocyte; cytology; drug effect; drug resistance; female; genetics; human; immunology; knockout mouse; metabolism; mortality; mouse; natural killer T cell; ovary tumor; pathology; signal transduction; survival rate; tumor microenvironment; Animals; B7-H1 Antigen; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; DNA (Cytosine-5-)-Methyltransferases; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Interferon-gamma; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Ovarian Neoplasms; Signal Transduction; Survival Rate; Tumor Microenvironment
Type
journal article