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

Cell | Nov 30, 2017

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.

Pubmed ID: 29195073 RIS Download

Mesh terms: Animals | Antigen Presentation | Antineoplastic Agents | Azacitidine | Carcinoma, Non-Small-Cell Lung | Cell Line, Tumor | Drug Therapy, Combination | Histone Deacetylase Inhibitors | Hydroxamic Acids | Immunotherapy | Lung Neoplasms | Mice | T-Lymphocytes | Transcriptome | Tumor Escape | Tumor Microenvironment

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Associated grants

  • Agency: NCI NIH HHS, Id: P30 CA006973
  • Agency: NCI NIH HHS, Id: U10 CA180950
  • Agency: NCI NIH HHS, Id: R01 CA121113
  • Agency: NCI NIH HHS, Id: R01 CA166348
  • Agency: NCI NIH HHS, Id: P30 CA008748

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