BRD4‐IRF1 axis regulates chemoradiotherapy‐induced PD‐L1 expression and immune evasion in non‐small cell lung cancer. Issue 1 (26th January 2022)

• Record Type: Journal Article
• Authors: Wang, Jian; Xu, Yingzhuo; Rao, Xinrui; Zhang, Ruiguang; Tang, Jing; Zhang, Dan; Jie, Xiaohua; Zhu, Kuikui; Wang, Xu; Xu, Yunhong; Zhang, Sheng; Dong, Xiaorong; Zhang, Tao; Yang, Kunyu; Xu, Shuangbing; Meng, Rui; Wu, Gang
• Is Part Of: Clinical and translational medicine. Volume 12:Issue 1(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-01-26
• Subjects: BRD4 -- cisplatin -- non‐small cell lung cancer -- PD‐L1 -- radiotherapy; Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.718
• Languages: English
• ISSNs: 2001-1326

Abstract

Abstract : 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. Abstract : (1) The flow cytometry‐based drug screening experiments showed that bromodomain Containing 4 (BRD4) inhibitors can simultaneously reverse the expression of PD‐L1 in NSCLC tumour cells induced by radiotherapy and cisplatin treatment. (2) Radiotherapy and chemotherapy up‐regulating PD‐L1 expression via the BRD4/IRF1 axis in NSCLC. (3) Targeting BRD4 boosted anti‐tumour immunity of chemoradiotherapy dependent on CD8+ T cells in vivo.