Fibrotic immune microenvironment remodeling mediates superior anti-tumor efficacy of a nano-PD-L1 trap in hepatocellular carcinoma

作者全名："Liu, Xiaoyu; Zhou, Jingying; Wu, Haoran; Chen, Shufen; Zhang, Lingyun; Tang, Wenshu; Duan, Liang; Wang, Ying; McCabe, Eleanor; Hu, Mengying; Yu, Zhuo; Liu, Hanzhuang; Choi, Chung Hang Jonathan; Sung, Joseph Jao-yiu; Huang, Leaf; Liu, Rihe; Cheng, Alfred Sze-lok"

作者地址："[Liu, Xiaoyu; Zhou, Jingying; Wu, Haoran; Chen, Shufen; Zhang, Lingyun; Tang, Wenshu; Cheng, Alfred Sze-lok] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong 999077, Peoples R China; [Duan, Liang] Chongqing Med Univ, Affiliated Hosp 2, Dept Lab Med, Chongqing 400010, Peoples R China; [Wang, Ying; McCabe, Eleanor; Liu, Rihe] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA; [Hu, Mengying; Huang, Leaf] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacoengn & Mol Pharmaceut, Chapel Hill, NC 27599 USA; [Yu, Zhuo] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Liver Dis, Shanghai 201203, Peoples R China; [Liu, Hanzhuang; Choi, Chung Hang Jonathan] Chinese Univ Hong Kong, Dept Biomed Engn, Hong Kong 999077, Peoples R China; [Sung, Joseph Jao-yiu] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 639798, Singapore; [Sung, Joseph Jao-yiu] Chinese Univ Hong Kong, State Key Lab Digest Dis, Hong Kong 999077, Peoples R China; [Cheng, Alfred Sze-lok] Chinese Univ Hong Kong, Shatin, Rm 406A, Lo Kwee Seong Integrated Biomed Sci Bldg,, Hong Kong, Peoples R China"

通信作者："Cheng, ASL (通讯作者)，Chinese Univ Hong Kong, Shatin, Rm 406A, Lo Kwee Seong Integrated Biomed Sci Bldg,, Hong Kong, Peoples R China."

来源：MOLECULAR THERAPY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000965009900001

JCR分区：Q1

影响因子：12.4

年份：2023

卷号：31

期号：1

开始页：119

结束页：133

文献类型：Article

关键词：　

摘要："The local microenvironment where tumors develop can shape cancer progression and therapeutic outcome. Emerging evi-dence demonstrate that the efficacy of immune-checkpoint blockade (ICB) is undermined by fibrotic tumor microenviron-ment (TME). The majority of hepatocellular carcinoma (HCC) develops in liver fibrosis, in which the stromal and immune components may form a barricade against immunotherapy. Here, we report that nanodelivery of a programmed death-ligand 1 (PD-L1) trap gene exerts superior efficacy in treating fibrosis-associated HCC when compared with the conventional monoclonal antibody (mAb). In two fibrosis-associated HCC models induced by carbon tetrachloride and a high-fat, high -carbohydrate diet, the PD-L1 trap induced significantly larger tumor regression than mAb with no evidence of toxicity. Mech-anistic studies revealed that PD-L1 trap, but not mAb, consis-tently reduced the M2 macrophage proportion in the fibrotic liver microenvironment and promoted cytotoxic interferon gamma (IFNg)+tumor necrosis factor a (TNF-a)+CD8+T cell infiltration to the tumor. Moreover, PD-L1 trap treatment was associated with decreased tumor-infiltrating polymorpho-nuclear myeloid-derived suppressor cell (PMN-MDSC) accu-mulation, resulting in an inflamed TME with a high cytotoxic CD8+T cell/PMN-MDSC ratio conductive to anti-tumor im-mune response. Single-cell RNA sequencing analysis of two clinical cohorts demonstrated preferential PD-L1 expression in M2 macrophages in the fibrotic liver, thus supporting the translational potential of nano-PD-L1 trap for fibrotic HCC treatment."

基金机构："Health and Medical Research Fund [16170451, 07180556]; Collaborative Research Fund; General Research Fund; Li Ka Shing Foundation; NIH/NCI; [C4045-18W]; [14120621]; [CA151652]"

基金资助正文："This study was supported by the Health and Medical Research Fund (16170451 to A.S.-l.C. and 07180556 to J.Z.), Collaborative Research Fund (C4045-18W to A.S.-l.C.), General Research Fund (14120621 to A.S.-l.C.), Li Ka Shing Foundation (to A.S.-l.C.), and NIH/NCI (CA151652 to R.L.)."