RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
BMP9 诱导的血管正常化提高了针对乙型肝炎病毒相关肝细胞癌的免疫治疗疗效
英文原题：BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma.
查看英文原题
BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma.
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研究概要
HBV 诱导的 BMP9 下调导致血管异常，从而抑制瘤内细胞毒性淋巴细胞浸润，这为开发免疫疗法并与基于 BMP9 的疗法联合治疗 HBV 相关 HCC 提供了依据。
研究思路结论见上方概要
背景
在过去十年中，肿瘤免疫治疗领域取得了巨大进展。然而，免疫检查点阻断（ICB）在肝细胞癌（HCC）治疗中的疗效仍然有限。细胞毒性淋巴细胞向肿瘤的转运对于ICB的成功至关重要。因此，迫切需要额外的策略来增加细胞毒性淋巴细胞向肿瘤的转运，以改善患者的免疫反应。
方法
对配对相邻组织和HBV相关HCC癌灶进行了RNA-seq分析。通过Cytoscape软件、临床标本和HCC的Gene Expression Omnibus (GEO)数据集，鉴定出反映血管正常化的骨形态发生蛋白(BMP9)。在细胞和动物中评估了BMP9对肿瘤血管系统的功能影响及机制。采用超声靶向微泡破坏(UTMD)介导的BMP9递送策略来正常化血管系统，并在免疫缺陷小鼠的人类癌症异种移植瘤中评估由细胞毒性淋巴细胞(NK细胞)联合PD-L1抗体介导的治疗疗效。
结果
我们发现，HBV感染诱导的BMP9表达下调与HCC患者的不良预后和病理性血管异常相关。在HBV感染的HCC细胞中过表达BMP9，可通过抑制Rho-ROCK-肌球蛋白轻链（MLC）信号级联反应实现血管正常化，从而促进瘤内细胞毒性淋巴细胞浸润，最终增强免疫治疗的疗效。此外，UTMD介导的BMP9递送恢复了细胞毒性淋巴细胞（NK细胞）的抗肿瘤功能，并在免疫缺陷小鼠的人类癌症异种移植模型中与PD-L1抗体联合显示出治疗效果。
展开英文摘要原文
BACKGROUND
In 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.
METHODS
Paired 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.
RESULTS
We 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.
CONCLUSIONS
HBV-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.
论文信息
- 作者
- Han Y、Pan Q、Guo Z、Du Y、Zhang Y、Liu Y、Zhao J、Xu J
- 单位
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Clinical and translational medicine2023 May
- 原文标识
- PubMed 37132170 · DOI 10.1002/ctm2.1247
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