13
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Synergistic immunostimulatory effects and therapeutic benefit of combined histone deacetylase and bromodomain inhibition in non-small cell lung cancer

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.

          Related collections

          Author and article information

          Journal
          101561693
          39259
          Cancer Discov
          Cancer Discov
          Cancer discovery
          2159-8274
          2159-8290
          11 May 2017
          13 April 2017
          August 2017
          01 February 2018
          : 7
          : 8
          : 852-867
          Affiliations
          [1 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
          [2 ]Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts
          [3 ]Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
          [4 ]Harvard Chan school of Public Health, Boston, Massachusetts
          [5 ]Acetylon Pharmaceuticals, Inc., Boston, Massachusetts
          [6 ]Laura & Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York
          Author notes
          Corresponding author: Kwok-Kin Wong, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115. Phone: 617-632-6084; Fax: 617-582-7839; kwong1@ 123456partners.org
          [*]

          These authors contributed equally to this work

          [%]

          Yuyang Li’s current address: Shandong Provincial Hospital, Shandong University, Jinan, China

          Article
          PMC5540748 PMC5540748 5540748 nihpa869167
          10.1158/2159-8290.CD-16-1020
          5540748
          28408401
          f3a993c1-e60a-4a20-9538-f5a6edbe4c2e

          Reprints and permissions information is available at www.nature.com/nm.

          History
          Categories
          Article

          Bromodomain inhibitor,Non-small cell lung cancer,immunomodulatory,immunotherapy,Histone deacetylase inhibitor

          Comments

          Comment on this article