Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, People's Republic of China.
Gut. 2024 May 10;73(6):985-999. doi: 10.1136/gutjnl-2023-331342.
The gain of function (GOF) CTNNB1 mutations (CTNNB1 ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC.
RNA sequencing was performed to identify the key downstream genes of CTNNB1 associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9.
MMP9 was significantly upregulated in CTNNB1 HCC. MMP9 suppressed infiltration and cytotoxicity of CD8 T cells, which was critical for CTNNB1 to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 downregulated sirtuin 2 (SIRT2), resulting in promotion of β-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8 T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC.
CTNNB1 induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 HCC.
在肝细胞癌（HCC）中，功能获得性（GOF）CTNNB1 突变（CTNNB1）导致显著的免疫逃逸和抗 PD-1 耐药。在此，我们旨在研究 CTNNB1 HCC 介导免疫逃逸的机制，并提出一种新的治疗策略来增强 HCC 中抗 PD-1 的疗效。
进行 RNA 测序以鉴定与免疫逃逸相关的 CTNNB1 下游关键基因。体外共培养系统、小鼠皮下或原位模型、条件性基因敲除小鼠的自发致瘤模型以及流式细胞术用于探索基质金属蛋白酶 9（MMP9）在肿瘤进展和免疫逃逸中的生物学功能。单细胞 RNA 测序和蛋白质组学用于深入了解 MMP9 的潜在机制。
MMP9 在 CTNNB1 HCC 中显著上调。MMP9 抑制 CD8 T 细胞的浸润和细胞毒性，这对于 CTNNB1 驱动抑制性肿瘤免疫微环境（TIME）和抗 PD-1 耐药至关重要。在机制上，CTNNB1 下调了沉默信息调节因子 2（SIRT2），导致 β-连环蛋白/赖氨酸去甲基酶 4D（KDM4D）复合物形成增加，从而促进 MMP9 的转录激活。HCC 分泌的 MMP9 介导了滑动蛋白磷酸酶 1（SSH1）从 CD8 T 细胞上的脱落，导致 C-X-C 基序趋化因子受体 3（CXCR3）介导的 G 蛋白偶联受体信号的细胞内抑制。此外，MMP9 阻断重塑了 TIME，并增强了 HCC 中抗 PD-1 治疗的敏感性。
CTNNB1 通过激活 MMP9 的分泌诱导抑制性 TIME。靶向 MMP9 重塑 TIME，并增强 CTNNB1 HCC 中抗 PD-1 的疗效。
