Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer Journal Article
| Authors: | Topper, M. J.; Vaz, M.; Chiappinelli, K. B.; DeStefano Shields, C. E.; Niknafs, N.; Yen, R. W. C.; Wenzel, A.; Hicks, J.; Ballew, M.; Stone, M.; Tran, P. T.; Zahnow, C. A.; Hellmann, M. D.; Anagnostou, V.; Strissel, P. L.; Strick, R.; Velculescu, V. E.; Baylin, S. B. |
| Article Title: | Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer |
| 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. Myc depletion through combined epigenetic therapy reverses immune evasion and enables effective treatment of lung cancer. © 2017 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; unclassified drug; human cell; genetics; histone deacetylase inhibitor; nonhuman; antineoplastic agents; alpha interferon; antineoplastic agent; lymphocyte proliferation; t lymphocyte; t-lymphocytes; mouse; phenotype; animal; animals; mice; animal tissue; protein depletion; carcinoma, non-small-cell lung; lung neoplasms; animal experiment; animal model; lung cancer; in vivo study; antineoplastic activity; in vitro study; cell line, tumor; lung tumor; antigen presentation; immunology; immune response; antigen; immunotherapy; drug therapy, combination; epigenetics; myc protein; tumor cell line; gene therapy; histone deacetylase inhibitors; hydroxamic acids; protein induction; upregulation; maximum plasma concentration; drug half life; enzyme specificity; transcriptome; beta interferon; isoprotein; chemoattractant; hydroxamic acid; suppressor cell; azacitidine; double stranded rna; myc; non small cell lung cancer; nsclc; tumor microenvironment; mocetinostat; immune evasion; givinostat; entinostat; enzyme repression; rantes; dna methyltransferase inhibitor; tumor escape; exhaustion; hdac; drug effects; combination drug therapy; human; male; female; priority journal; article; lung cancer cell line; memory t cells; itf-2357; rgfp 996; tubastatin a; givinostat hydrochloride |
| Journal Title: | Cell |
| Volume: | 171 |
| Issue: | 6 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2017-11-30 |
| Start Page: | 1284 |
| End Page: | 1300.e21 |
| Language: | English |
| DOI: | 10.1016/j.cell.2017.10.022 |
| PUBMED: | 29195073 |
| PROVIDER: | scopus |
| PMCID: | PMC5808406 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
