Journal
CLINICAL AND TRANSLATIONAL MEDICINE
Volume 12, Issue 1, Pages -Publisher
JOHN WILEY & SONS LTD
DOI: 10.1002/ctm2.718
Keywords
BRD4; cisplatin; non-small cell lung cancer; PD-L1; radiotherapy
Categories
Funding
- National Natural Science Foundation of China [81874218, 81672979, 81472201]
- Wuhan Science and Technology Bureau [2018060401011318]
- Wu Jieping Medical Foundation [320.6750.15007]
- Special Fund for Technological Innovation of Hubei [2020BCA068]
Ask authors/readers for more resources
The study showed that targeting BRD4 synergized with chemoradiotherapy and anti-PD-1 antibody to enhance anti-tumour immunity in NSCLC. BRD4 inhibitors JQ1 and ARV-771 were identified to suppress cisplatin and radiation-induced PD-L1 expression. Disrupting recruitment of BRD4-IRF1 complex to PD-L1 promoter was proposed as the mechanism of BRD4 inhibition on chemoradiation-induced PD-L1 expression. In vivo experiments demonstrated that BRD4 inhibition combined with chemoradiotherapy and PD-1 blockade resulted in a robust anti-tumour immunity without increased toxicities.
Background Chemoradiotherapy-induced PD-L1 upregulation leads to therapeutic resistance and treatment failure. The PD-1/PD-L1 blocking antibodies sensitize cancers to chemoradiotherapy by blocking extracellular PD-1 and PD-L1 binding without affecting the oncogenic function of intracellular PD-L1. Reversing the chemoradiation-induced PD-L1 expression could provide a new strategy to achieve a greater anti-tumour effect of chemoradiotherapy. Here, we aimed to identify candidate small molecular inhibitors that might boost the anti-tumour immunity of chemoradiotherapy by decreasing treatment-induced PD-L1 expression in non-small cell lung cancer (NSCLC). Methods A drug array was used to recognize compounds that can suppress the cisplatin-induced and radiation-induced PD-L1 expression in NSCLC via the flow cytometry-based assay. We examined whether and how targeting bromodomain containing 4 (BRD4) inhibits chemoradiation-induced PD-L1 expression and evaluated the effect of BRD4 inhibition and chemoradiation combination in vivo. Results BRD4 inhibitors JQ1 and ARV-771 were identified as the most promising drugs both in the cisplatin and radiation screening projects in two NSCLC cell lines. Targeting BRD4 was supposed to block chemoradiotherapy inducible PD-L1 expression by disrupting the recruitment of BRD4-IRF1 complex to PD-L1 promoter. A positive correlation between BRD4 and PD-L1 expression was observed in human NSCLC tissues. Moreover, BRD4 inhibition synergized with chemoradiotherapy and PD-1 blockade to show a robust anti-tumour immunity dependent on CD8+ T cell through limiting chemoradiation-induced tumour cell surface PD-L1 upregulation in vivo. Notably, the BRD4-targeted combinatory treatments did not show increased toxicities. Conclusion The data showed that BRD4-targeted therapy synergized with chemoradiotherapy and anti-PD-1 antibody by boosting anti-tumour immunity in NSCLC.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available