Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer
Menée à l'aide de lignées cellulaires de cancer du poumon non à petites cellules et à l'aide de modèles murins, cette étude montre qu'un traitement combinant un inhibiteur d'histone désacétylase et un inhibiteur de l'ADN méthyltransférase induit une réduction du niveau du facteur de transcription MYC et inverse le processus d'échappement immunitaire
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/?-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.
Cell 2017