EPIGENETIC THERAPY TIES MYC DEPLETION TO REVERSING IMMUNE EVASION AND TREATING LUNG CANCER

MYC;Epigenetic;Human Genetics and Molecular Biology

Topper, Michael JonathanCasero, Robert ;

Johns Hopkins University

关键词: MYC;    Epigenetic;    Human Genetics and Molecular Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60923/TOPPER-DISSERTATION-2018.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Combining DNA demethylating agents (DNMTis) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACi’s are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen which imparts a robust anti-tumor effect for non-small cell lung cancer (NSCLC). Using in vitro treated NSCLC cell lines, we elucidate an Interferon-αβ based transcriptional program with accompanying upregulation of antigen presentation machinery mediated in part through 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.