Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Cell, 2017-11, Vol.171 (6), p.1284-1300.e21

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •Azacitidine depletes MYC and sensitizes NSCLC to HDACi•Combination epigenetic treatment induces a potent anti-tumor response in vivo•Epigenetic treatment potentiates anti-tumor responses by modulating T cell phenotypes•MYC status determines tumor immunophenotype Myc depletion through combined epigenetic therapy reverses immune evasion and enables effective treatment of lung cancer.