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Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer.
- Source :
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Cancer discovery [Cancer Discov] 2017 Aug; Vol. 7 (8), pp. 852-867. Date of Electronic Publication: 2017 Apr 13. - Publication Year :
- 2017
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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 <superscript>+</superscript> FOXP3 <superscript>+</superscript> 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 antitumor immunity and demonstrate their therapeutic potential for treatment of NSCLC. Significance: Selective inhibition of HDACs and bromodomain proteins modulates tumor-associated immune cells in a manner that favors improved T-cell function and reduced inhibitory cellular mechanisms. These effects facilitated robust antitumor responses in tumor-bearing mice, demonstrating the therapeutic potential of combining these epigenetic modulators for the treatment of NSCLC. Cancer Discov; 7(8); 852-67. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 783 .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Aged
Animals
Antineoplastic Combined Chemotherapy Protocols adverse effects
Apoptosis drug effects
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung immunology
Carcinoma, Non-Small-Cell Lung pathology
Cell Line, Tumor
Cell Proliferation drug effects
Drug Synergism
Female
Histone Deacetylases genetics
Histone Deacetylases immunology
Humans
Hydroxamic Acids adverse effects
Immunotherapy
Lymphocytes, Tumor-Infiltrating drug effects
Lymphocytes, Tumor-Infiltrating immunology
Male
Mice
Middle Aged
Pyrimidines adverse effects
Xenograft Model Antitumor Assays
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Carcinoma, Non-Small-Cell Lung drug therapy
Histone Deacetylase Inhibitors administration & dosage
Hydroxamic Acids administration & dosage
Pyrimidines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 7
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 28408401
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-16-1020