BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma

Han, Yulong1; Pan, Qiuzhong1; Guo, Zhixing1,2; Du, Yufei1; Zhang, Yaojun3; Liu, Yingying4; Zhao, Jingjing1; Xu, Jinfeng4; Yang, Jieying1; Ouyang, Dijun1; Tang, Yan1; Wang, Qijing1; Li, Yongqiang1; He, Jia1; Yang, Mengjuan1; Chen, Hao1; Yang, Chaopin1; Yang, Xinyi1; You, Jinqi1; Chen, Yuanyuan1; Ren, Minghao5; Zhu, Yao6; Xia, Jianchuan1,8; Xiang, Tong1,7

2023-05-01

10.1002/ctm2.1247

CLINICAL AND TRANSLATIONAL MEDICINE   影响因子和分区

2001-1326

BackgroundIn the past decade, the field of tumour immunotherapy has made a great progress. However, the efficacy of immune checkpoint blocking (ICB) in the treatment of hepatocellular carcinoma (HCC) remains limited. Cytotoxic lymphocyte trafficking into tumours is critical for the success of ICB. Therefore, additional strategies that increase cytotoxic lymphocyte trafficking into tumours are urgently needed to improve patient immune responses. MethodsPaired adjacent tissue and cancerous lesions with HBV-associated HCC were subjected to RNA-seq analysis. Bone morphogenetic protein (BMP9), which reflects vessel normalisation, was identified through Cytoscape software, clinical specimens and Gene Expression Omnibus (GEO) datasets for HCC. The functional effects and mechanism of BMP9 on the tumour vasculature were evaluated in cells and animals. An ultrasound-targeted microbubble destruction (UTMD)-mediated BMP9 delivery strategy was used to normalise the vasculature and evaluate therapeutic efficacy mediated by cytotoxic lymphocytes (NK cells) in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. ResultsWe discovered that hepatitis B virus (HBV) infection-induced downregulation of BMP9 expression correlated with a poor prognosis and pathological vascular abnormalities in patients with HCC. BMP9 overexpression in HBV-infected HCC cells promoted intra-tumoural cytotoxic lymphocyte infiltration via vascular normalisation by inhibiting the Rho-ROCK-myosin light chain (MLC) signalling cascade, resulting in enhanced efficacy of immunotherapy. Furthermore, UTMD-mediated BMP9 delivery restored the anti-tumour function of cytotoxic lymphocytes (NK cells) and showed therapeutic efficacy in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. ConclusionsHBV-induced BMP9 downregulation causes vascular abnormalities that inhibit intra-tumoural cytotoxic lymphocyte infiltration, providing a rationale for developing and combining immunotherapy with BMP9-based therapy to treat HBV-associated HCC.

BMP9 HBV-associated HCC immunotherapy vascular normalisation

SCI

英语

其他

National Natural Science Foundation of China["GZR2021-029","L102012021008U"] ; null[81874129] ; null[82172795]

Oncology ; Research & Experimental Medicine

Oncology ; Medicine, Research & Experimental

WOS:001001457900002

JOHN WILEY & SONS LTD

Web of Science

1.Sun Yat Sen Univ, Dept Expt Res, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med,Guangdong Key Lab, Guangzhou, Guangdong, Peoples R China
2.Sun Yat Sen Univ, Dept Ultrasound, Canc Ctr, Guangzhou, Guangdong, Peoples R China
3.Sun Yat Sen Univ, Dept Hepatobiliary Surg, Canc Ctr, Guangzhou, Guangdong, Peoples R China
4.Southern Univ Sci & Technol, Dept Ultrasonog, Shenzhen Med Ultrasound Engn Ctr, Shenzhen Peoples Hosp,Clin Med Coll 2,Clin Med Col, Shenzhen, Guangdong, Peoples R China
5.Shandong Qilu Stem Cell Engn Co Ltd, Applicat Business Div, Zibo, Shandong, Peoples R China
6.Shenzhen MSU BIT Univ, Dept Mat Sci, Shenzhen, Guangdong, Peoples R China
7.Sun Yat Sen Univ, Dept Expt Res, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med,Guangdong Key Lab, Guangzhou 510060, Guangdong, Peoples R China
8.Sun Yat Sen Univ, Canc Ctr, Guangzhou 510060, Guangdong, Peoples R China

Han, Yulong,Pan, Qiuzhong,Guo, Zhixing,et al. BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma[J]. CLINICAL AND TRANSLATIONAL MEDICINE,2023,13(5).

Han, Yulong.,Pan, Qiuzhong.,Guo, Zhixing.,Du, Yufei.,Zhang, Yaojun.,...&Xiang, Tong.(2023).BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma.CLINICAL AND TRANSLATIONAL MEDICINE,13(5).

Han, Yulong,et al."BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma".CLINICAL AND TRANSLATIONAL MEDICINE 13.5(2023).