FEB 21, 2018 10:30 AM PST

The Effects of Epigenetic Therapies on the Tumor and Host Immune System

Presented at: Drug Discovery 2018
Speaker
  • Assistant Professor of Microbiology, Immunology, & Tropical Medicine at The George Washington University
    Biography
      Katherine Bakshian Chiappinelli, Ph.D., joined the GW Department of Microbiology, Immunology and Tropical Medicine University in 2017 as an Assistant Professor.Dr. Chiappinelli graduated with a B.S. in Biology and Music from Haverford College in 2007 and received her Ph.D. in Developmental, Regenerative, and Stem Cell Biology from Washington University in St. Louis under the supervision of Dr. Paul Goodfellow in 2012. Dr. Chiappinelli pursued postdoctoral studies at Johns Hopkins University with Dr. Stephen Baylin investigating the epigenetic control of immune signaling in cancer cells. Her research focuses on how epigenetic therapies can be used against cancers, specifically in the context of arming the host immune system to fight cancer cells.

    Abstract

    Therapies that activate the host immune system have shown tremendous promise for a wide variety of solid tumors. However, in most cancer types, fewer than half of patients respond to these therapies. Epigenetic therapy can increase immune signaling from tumors, sensitizing to immune therapy in mouse models of cancer. DNA methyltransferase inhibitors (DNMTis) upregulate interferon signaling in solid tumors by cytosolic sensing of double-stranded RNA (dsRNA), triggering a Type I Interferon response and apoptosis. Demethylation and expression of bidirectionally transcribed endogenous retroviruses (ERVs) is a major component of the dsRNA that activates the response. Adding histone deacetylase inhibitors (HDACis) to DNMTis can augment this upregulation. In mouse models of cancer, DNMTi stimulate the interferon response through ERV upregulation, leading to  increased recruitment of T cells, including tumor-killing T Effector (CD3+CD8+) cells, to the tumor. This epigenetic therapy causes increased activation of CD8 T cells and natural killer cells, an increase in helper T cells, and a reduction in suppressive myeloid cells. Both the immune cell activation and the tumor burden decrease by DNMTi are dependent on activation of the Type I Interferon response and are associated with an increase in transcription of mouse ERVs. Treatment of this mouse model with the above drug combination plus anti-PD-1 significantly reduces tumor burden and increases survival. Separately, EZH2 inhibitors can increase signaling from tumor cells to recruit immune cells to kill tumors. Lastly, DNMTis can directly affect methylation on T cells to reverse T cell exhaustion. This presentation will cover work from our group and others on the use of epigenetic therapies to reverse immune evasion in cancers. 


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