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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1284-1300.e21
JournalCell
Volume171
Issue number6
DOIs
StatePublished - Nov 30 2017

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Topper, M. J., Vaz, M., Chiappinelli, K. B., DeStefano Shields, C. E., Niknafs, N., Yen, R. W. C., Wenzel, A., Hicks, J., Ballew, M., Stone, M., Tran, P. T., Zahnow, C. A., Hellmann, M. D., Anagnostou, V., Strissel, P. L., Strick, R., Velculescu, V. E., & Baylin, S. B. (2017). Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer. Cell, 171(6), 1284-1300.e21. https://doi.org/10.1016/j.cell.2017.10.022