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  • Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer.

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer.

Scientific reports (2020-02-28)
Sara Moufarrij, Aneil Srivastava, Stephanie Gomez, Melissa Hadley, Erica Palmer, Paul Tran Austin, Sarah Chisholm, Noor Diab, Kyle Roche, Angela Yu, Jing Li, Wenge Zhu, Micael Lopez-Acevedo, Alejandro Villagra, Katherine B Chiappinelli
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cycloheximide solution, Ready-Made Solution, microbial, 100 mg/mL in DMSO, Suitable for cell culture
Sigma-Aldrich
Anti-DNMT1 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
TWEEN® 80, for molecular biology, syrup
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA Mn 55,000