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

Michael J Topper; Michelle Vaz; Katherine B Chiappinelli; Christina E DeStefano Shields; Noushin Niknafs; Ray-Whay Chiu Yen; Alyssa Wenzel; Jessica Hicks; Matthew Ballew; Meredith Stone; Phuoc T Tran; Cynthia A Zahnow; Matthew D Hellmann; Valsamo Anagnostou; Pamela L Strissel; Reiner Strick; Victor E Velculescu; Stephen B Baylin

doi:10.1016/j.cell.2017.10.022

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

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

Authors

Michael J Topper¹, Michelle Vaz², Katherine B Chiappinelli³, Christina E DeStefano Shields², Noushin Niknafs², Ray-Whay Chiu Yen², Alyssa Wenzel⁴, Jessica Hicks⁵, Matthew Ballew⁶, Meredith Stone¹, Phuoc T Tran⁶, Cynthia A Zahnow², Matthew D Hellmann⁷, Valsamo Anagnostou², Pamela L Strissel⁸, Reiner Strick⁸, Victor E Velculescu², Stephen B Baylin⁹

Affiliations

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.

MeSH terms

Animals
Antigen Presentation / drug effects
Antineoplastic Agents / therapeutic use
Azacitidine / therapeutic use
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / immunology
Carcinoma, Non-Small-Cell Lung / therapy*
Cell Line, Tumor
Drug Therapy, Combination*
Histone Deacetylase Inhibitors / therapeutic use
Hydroxamic Acids / therapeutic use
Immunotherapy
Lung Neoplasms / genetics
Lung Neoplasms / immunology
Lung Neoplasms / therapy*
Mice
T-Lymphocytes / immunology
Transcriptome
Tumor Escape / drug effects*
Tumor Microenvironment

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Hydroxamic Acids
Azacitidine
givinostat hydrochloride

Abstract

MeSH terms

Substances

Grants and funding