FEB 21, 2018 6:00 AM PST

Using HDAC Inhibitors to Improve Cancer Immunotherapy

Presented at: Drug Discovery 2018
Speaker
  • Assistant Professor of Biochemistry and Molecular Medicine, GW School of Medicine and Health Sciences
    Biography
      Dr. Villagra's areas of expertise are epigenetics and tumor immunology. During his early scientific career, he explored different aspects of epigenetic regulation including DNA methylation, ATP-dependent chromatin remodeling complexes, histone acetyltranferases and histone deacetylases. His study models have been diverse and have included myogenic and osteoblastic differentiation, gene regulation of immune-related pathways and tumor immunology. Over the last several years, his group has focused on the study of the role of different epigenetic modifiers in the modulation of anti-tumor immune responses, assigning a special emphasis to the identification of potential therapeutic agents to improve immunotherapy. Dr. Villagra's group experimental approaches have important translational components, which allow them the possibility to extend their research into the clinical area. These particular characteristics help provide continuous scientific feedback and keep goals focused on relevant biomedical aspects of research.

    Abstract

    We recently reported that HDAC6 is involved in the regulation of a number of immunosuppressive checkpoint proteins, including the Program Death Receptor Ligand 1 (PD-L1). This protein is one of the natural ligands for the PD-1 receptor present on T-cells, consistently reported to suppress T-cell activation, proliferation, and induce T-cell exhaustion, anergy and apoptosis. As a result, increased PD-L1 expression by cancer cells remains a fundamental escape mechanism from host immunity within the tumor microenvironment, and the understanding the molecular mechanisms modulating PD-L1 and other immunosuppressive mediators could lead to improved treatments for cancer patients. Several publications have linked the over-expression of PD-L1 in tumors and tumor microenvironment with a poor prognosis in several malignancies, including melanoma, ovarian, gastric and breast cancer, among many others. However, more detailed mechanistic information regarding the molecular events involved in the regulation of PD-L1 is still missing. Moreover, limited information is available about the participation of preclinical and clinical anti-cancer agents in the regulation of PD-L1 and other immunomodulatory pathways. As a result, this gap in knowledge is preventing the design of new immunotherapeutic combination therapies. Given the fact that HDAC6 is a potential regulator of immunosuppressive mediators, it opens up a new avenue for immunotherapy. By using selective HDAC6inh as adjuvants to ongoing immune blockade based treatments, we are aiming to further augment anti-tumor immune responses.   


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