@article{af07031b5cf74e7a9b6a0f852975bea9,
title = "Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer",
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. Myc depletion through combined epigenetic therapy reverses immune evasion and enables effective treatment of lung cancer.",
keywords = "HDAC, ITF-2357, MYC, NSCLC, azacitidine, immune response, lung cancer, memory T cells",
author = "Topper, {Michael J.} and Michelle Vaz and Chiappinelli, {Katherine B.} and {DeStefano Shields}, {Christina E.} and Noushin Niknafs and Yen, {Ray Whay Chiu} and Alyssa Wenzel and Jessica Hicks and Matthew Ballew and Meredith Stone and Tran, {Phuoc T.} and Zahnow, {Cynthia A.} and Hellmann, {Matthew D.} and Valsamo Anagnostou and Strissel, {Pamela L.} and Reiner Strick and Velculescu, {Victor E.} and Baylin, {Stephen B.}",
note = "Funding Information: This work was supported by grants from The Hodson Trust , The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation , The Commonwealth Foundation , Stand Up To Cancer Jim Toth Sr. Breakthrough Prize in Lung Cancer , and the SWCRF Collaboration for a Cure . This work is also supported by The Defense Health Program ( DOD0 ), through the Department of Defense Ovarian Cancer Research Program , Teal Innovator Award No. OC130454/W81XWH-14-1-0385 (opinions, interpretations, conclusions, and recommendations are those of the author and not necessarily endorsed by the Department of Defense). Research reported in this publication was supported by the National Cancer Institute under award numbers CA121113 , CA006973 , and CA180950 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH . Research funding was also provided by the Van Andel Research Institute through the Van Andel Research Institute – Stand Up To Cancer Epigenetics Dream Team . Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by AACR. We acknowledge Mrs. Elizabeth Stiegler and Lauren Murphy for expert technical help. We thank Kathy Bender for help with manuscript preparation. V.E.V. is a founder of Personal Genome Diagnostics, a member of its Scientific Advisory Board and Board of Directors, and owns Personal Genome Diagnostics stock, which is subject to certain restrictions under university policy. V.E.V. is also on the Scientific Advisory Board for Ignyta. Funding Information: This work was supported by grants from The Hodson Trust, The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, The Commonwealth Foundation, Stand Up To Cancer Jim Toth Sr. Breakthrough Prize in Lung Cancer, and the SWCRF Collaboration for a Cure. This work is also supported by The Defense Health Program (DOD0), through the Department of Defense Ovarian Cancer Research Program, Teal Innovator Award No. OC130454/W81XWH-14-1-0385 (opinions, interpretations, conclusions, and recommendations are those of the author and not necessarily endorsed by the Department of Defense). Research reported in this publication was supported by the National Cancer Institute under award numbers CA121113, CA006973, and CA180950. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Research funding was also provided by the Van Andel Research Institute through the Van Andel Research Institute – Stand Up To Cancer Epigenetics Dream Team. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by AACR. We acknowledge Mrs. Elizabeth Stiegler and Lauren Murphy for expert technical help. We thank Kathy Bender for help with manuscript preparation. V.E.V. is a founder of Personal Genome Diagnostics, a member of its Scientific Advisory Board and Board of Directors, and owns Personal Genome Diagnostics stock, which is subject to certain restrictions under university policy. V.E.V. is also on the Scientific Advisory Board for Ignyta. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = nov,
day = "30",
doi = "10.1016/j.cell.2017.10.022",
language = "English (US)",
volume = "171",
pages = "1284--1300.e21",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}