Blockade of myeloid-derived suppressor cell function by valproic acid enhanced anti-PD-L1 tumor immunotherapy

被引:31
作者
Adeshakin, Adeleye O. [1 ,2 ]
Yan, Dehong [1 ]
Zhang, Mengqi [1 ,3 ]
Wang, Lulu [4 ]
Adeshakin, Funmilayo O. [1 ,2 ]
Liu, Wan [1 ]
Wan, Xiaochun [1 ,2 ]
机构
[1] Chinese Acad Sci, Ctr Prot & Cell Based Drugs, Shenzhen Inst Adv Technol, Shenzhen Lab Human Antibody Engn, Shenzhen 518055, Peoples R China
[2] Univ Chinese Acad Sci, Beijing 100864, Peoples R China
[3] Jinzhou Med Univ, Sch Basic Med Sci, Jinzhou 121000, Peoples R China
[4] Univ Hong Kong, Dept Pediat, Shenzhen Hosp, Shenzhen 518053, Peoples R China
基金
中国国家自然科学基金;
关键词
Valproic acid; Myeloid-derived suppressor cell; IRF1/IRF8; Anti-PD-L1 tumor immunotherapy; REGULATORY FACTOR-8; IL-10;
D O I
10.1016/j.bbrc.2019.11.155
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Regardless of the remarkable clinical success of immune checkpoint blockade (ICB) against PD-1/PD-L1 pathway, this approach has encountered drawbacks in most patients due to the activation of tumor immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Histone deacetylase (HDAC) inhibitors combat ICB resistance by attenuating the immunosuppressive function of MDSCs and increasing PD-L1 expression on tumor cells. However, whether an HDAC inhibitor - valproic acid (VPA) suppression of MDSCs function could enhance PD-L1 blockade-mediated tumor immunotherapy remains unknown. Here we report that VPA and anti-PD-L1 antibody combined treatment promoted the polarization of bone marrow-derived precursor cells into M-MDSCs. Interestingly, the combination treatment of VPA and anti-PD-L1 antibody activated IRF1/IRF8 transcriptional axis in MDSCs leading to blockade of their immunosuppressive function by downregulating the expression of IL-10, IL-6, and ARG1 while reactivating CD8(+)T-cells for the production of TNIF alpha to further enhance anti-tumor immunity. These observations provide further rationale for the combination therapy of VPA with anti-PD-L1 antibody in preclinical settings. (C) 2019 Elsevier Inc. All rights reserved.
引用
收藏
页码:604 / 611
页数:8
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