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Cell. 2017 Nov 30;171(6):1284-1300.e21. doi: 10.1016/j.cell.2017.10.022.

Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer.

Author information

1
Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA; The Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA.
3
Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University Cancer Center, Washington, DC 20052, USA.
4
The Johns Hopkins University, Baltimore, MD 21218, USA.
5
Department of Urologic Pathology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA.
6
Department of Radiation Oncology & Molecular Radiation Sciences, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA.
7
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Department of Gynecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
9
Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu.

Abstract

Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.

KEYWORDS:

HDAC; ITF-2357; MYC; NSCLC; azacitidine; immune response; lung cancer; memory T cells

PMID:
29195073
PMCID:
PMC5808406
DOI:
10.1016/j.cell.2017.10.022
[Indexed for MEDLINE]
Free PMC Article

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