TGF-β1 诱导的 SOX18 升高通过转录上调 PD-L1 和 CXCL12 促进肝细胞癌的进展和转移。
TGF-β1-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression and Metastasis Through Transcriptionally Upregulating PD-L1 and CXCL12.
机构信息
Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
出版信息
Gastroenterology. 2024 Jul;167(2):264-280. doi: 10.1053/j.gastro.2024.02.025. Epub 2024 Feb 27.
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is characterized by an immune-suppressive microenvironment, which contributes to tumor progression, metastasis, and immunotherapy resistance. Identification of HCC-intrinsic factors regulating the immunosuppressive microenvironment is urgently needed. Here, we aimed to elucidate the role of SYR-Related High-Mobility Group Box 18 (SOX18) in inducing immunosuppression and to validate novel combination strategies for SOX18-mediated HCC progression and metastasis.
METHODS
The role of SOX18 in HCC was investigated in orthotopic allografts and diethylinitrosamine/carbon tetrachloride-induced spontaneous models by using murine cell lines, adeno-associated virus 8, and hepatocyte-specific knockin and knockout mice. The immune cellular composition in the HCC microenvironment was evaluated by flow cytometry and immunofluorescence.
RESULTS
SOX18 overexpression promoted the infiltration of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) while diminishing cytotoxic T cells to facilitate HCC progression and metastasis in cell-derived allografts and chemically induced HCC models. Mechanistically, transforming growth factor-beta 1 (TGF-β1) upregulated SOX18 expression by activating the Smad2/3 complex. SOX18 transactivated chemokine (C-X-C motif) ligand 12 (CXCL12) and programmed death ligand 1 (PD-L1) to induce the immunosuppressive microenvironment. CXCL12 knockdown significantly attenuated SOX18-induced TAMs and Tregs accumulation and HCC dissemination. Antagonism of chemokine receptor 4 (CXCR4), the cognate receptor of CXCL12, or selective knockout of CXCR4 in TAMs or Tregs likewise abolished SOX18-mediated effects. TGFβR1 inhibitor Vactosertib or CXCR4 inhibitor AMD3100 in combination with anti-PD-L1 dramatically inhibited SOX18-mediated HCC progression and metastasis.
CONCLUSIONS
SOX18 promoted the accumulation of immunosuppressive TAMs and Tregs in the microenvironment by transactivating CXCL12 and PD-L1. CXCR4 inhibitor or TGFβR1 inhibitor in synergy with anti-PD-L1 represented a promising combination strategy to suppress HCC progression and metastasis.
背景与目的
肝细胞癌（HCC）的特征是免疫抑制微环境，这有助于肿瘤的进展、转移和免疫治疗耐药。迫切需要鉴定调节免疫抑制微环境的 HCC 内在因素。在这里，我们旨在阐明 SYR 相关高迁移率族框 18（SOX18）在诱导免疫抑制中的作用，并验证新型 SOX18 介导的 HCC 进展和转移的联合策略。
方法
通过使用鼠源细胞系、腺相关病毒 8、肝细胞特异性敲入和敲除小鼠，在原位同种异体移植和二乙基亚硝胺/四氯化碳诱导的自发性模型中研究 SOX18 在 HCC 中的作用。通过流式细胞术和免疫荧光评估 HCC 微环境中的免疫细胞组成。
结果
SOX18 过表达促进肿瘤相关巨噬细胞（TAMs）和调节性 T 细胞（Tregs）的浸润，同时减少细胞源性同种异体移植和化学诱导 HCC 模型中的细胞毒性 T 细胞，从而促进 HCC 的进展和转移。机制上，转化生长因子-β1（TGF-β1）通过激活 Smad2/3 复合物上调 SOX18 的表达。SOX18 反式激活趋化因子（C-X-C 基序）配体 12（CXCL12）和程序性死亡配体 1（PD-L1）诱导免疫抑制微环境。CXCL12 敲低显著减弱了 SOX18 诱导的 TAMs 和 Tregs 积累和 HCC 播散。趋化因子受体 4（CXCR4），即 CXCL12 的同源受体的拮抗剂，或 TAMs 或 Tregs 中 CXCR4 的选择性敲除，同样消除了 SOX18 介导的作用。TGFβR1 抑制剂 Vactosertib 或 CXCR4 抑制剂 AMD3100 与抗 PD-L1 联合使用可显著抑制 SOX18 介导的 HCC 进展和转移。
结论
SOX18 通过反式激活 CXCL12 和 PD-L1 促进免疫抑制性 TAMs 和 Tregs 在微环境中的积累。CXCR4 抑制剂或 TGFβR1 抑制剂与抗 PD-L1 协同作用代表了抑制 HCC 进展和转移的有前途的联合策略。
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