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

Topper MJ, Vaz M, Chiappinelli KB, Shields CED, Niknafs N, Yen RWC, Wenzel A, Hicks J, Ballew M, Stone M, Tran PT, Zahnow CA, Hellmann MD, Anagnostou V, Strissel P, Strick R, Velculescu VE, Baylin SB (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Cell Elsevier

Book Volume: 171

Pages Range: 1284-1300.e21

Journal Issue: 6

DOI: 10.1016/j.cell.2017.10.022

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.

Authors with CRIS profile

Pamela Strissel Medizinische Fakultät Reiner Strick Medizinische Fakultät

Additional Organisation(s)

Lehrstuhl für Geburtshilfe und Frauenheilkunde

Involved external institutions

Johns Hopkins University (JHU) US United States (USA) (US) George Washington University (GWU) US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US)

How to cite

APA:

Topper, M.J., Vaz, M., Chiappinelli, K.B., Shields, C.E.D., Niknafs, N., Yen, R.-W.C.,... Baylin, S.B. (2017). Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer. Cell, 171(6), 1284-1300.e21. https://dx.doi.org/10.1016/j.cell.2017.10.022

MLA:

Topper, Michael J., et al. "Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer." Cell 171.6 (2017): 1284-1300.e21.

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