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

Author:
Topper, Michael J., Vaz, Michelle, Chiappinelli, Katherine B., DeStefano Shields, Christina E., Niknafs, Noushin, Yen, Ray-Whay Chiu, Wenzel, Alyssa, Hicks, Jessica, Ballew, Matthew, Stone, Meredith, Tran, Phuoc T., Zahnow, Cynthia A., Hellmann, Matthew D., Anagnostou, Valsamo, Strissel, Pamela L., Strick, Reiner, Velculescu, Victor E., Baylin, Stephen B.
Source:
Cell 2017 v.171 no.6 pp. 1284-1300.e21
ISSN:
0092-8674
Subject:
DNA, T-lymphocytes, animal models, antigen presentation, antineoplastic activity, cell lines, chemoattractants, chemokine CCL5, clinical trials, double-stranded RNA, enzyme inhibitors, epigenetics, gene expression regulation, histone deacetylase, immune evasion, interferons, lung neoplasms, memory, methyltransferases, phenotype, therapeutics, transcription (genetics)
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.
Agid:
6098985