SLFN11 缺失诱导的 CCL2 信号中断和巨噬细胞 M2 极化增强了抗 PD-1 治疗肝细胞癌的疗效。
Disruption of SLFN11 Deficiency-Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti-PD-1 Therapy Efficacy in Hepatocellular Carcinoma.
机构信息
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People's Republic of China; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, People's Republic of China.
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People's Republic of China; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, People's Republic of China.
出版信息
Gastroenterology. 2023 Jun;164(7):1261-1278. doi: 10.1053/j.gastro.2023.02.005. Epub 2023 Feb 28.
BACKGROUND & AIMS: The therapeutic effect of immune checkpoint inhibitors (ICIs) is poor in hepatocellular carcinoma (HCC) and varies greatly among individuals. Schlafen (SLFN) family members have important functions in immunity and oncology, but their roles in cancer immunobiology remain unclear. We aimed to investigate the role of the SLFN family in immune responses against HCC.
METHODS
Transcriptome analysis was performed in human HCC tissues with or without response to ICIs. A humanized orthotopic HCC mouse model and a co-culture system were constructed, and cytometry by time-of-flight technology was used to explore the function and mechanism of SLFN11 in the immune context of HCC.
RESULTS
SLFN11 was significantly up-regulated in tumors that responded to ICIs. Tumor-specific SLFN11 deficiency increased the infiltration of immunosuppressive macrophages and aggravated HCC progression. HCC cells with SLFN11 knockdown promoted macrophage migration and M2-like polarization in a C-C motif chemokine ligand 2-dependent manner, which in turn elevated their own PD-L1 expression by activating the nuclear factor-κB pathway. Mechanistically, SLFN11 suppressed the Notch pathway and C-C motif chemokine ligand 2 transcription by binding competitively with tripartite motif containing 21 to the RNA recognition motif 2 domain of RBM10, thereby inhibiting tripartite motif containing 21-mediated RBM10 degradation to stabilize RBM10 and promote NUMB exon 9 skipping. Pharmacologic antagonism of C-C motif chemokine receptor 2 potentiated the antitumor effect of anti-PD-1 in humanized mice bearing SLFN11 knockdown tumors. ICIs were more effective in patients with HCC with high serum SLFN11 levels.
CONCLUSIONS
SLFN11 serves as a critical regulator of microenvironmental immune properties and an effective predictive biomarker of ICIs response in HCC. Blockade of C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 signaling sensitized SLFN11 HCC patients to ICI treatment.
背景与目的
免疫检查点抑制剂（ICIs）在肝细胞癌（HCC）中的治疗效果不佳，且个体间差异较大。SLFN 家族成员在免疫和肿瘤学中具有重要功能，但它们在癌症免疫生物学中的作用尚不清楚。本研究旨在探讨 SLFN 家族在 HCC 免疫反应中的作用。
方法
对免疫检查点抑制剂治疗有反应或无反应的 HCC 组织进行转录组分析。构建了人源化原位 HCC 小鼠模型和共培养系统，并采用飞行时间技术的细胞术探索 SLFN11 在 HCC 免疫背景下的功能和机制。
结果
SLFN11 在对 ICIs 有反应的肿瘤中显著上调。肿瘤特异性 SLFN11 缺失增加了免疫抑制性巨噬细胞的浸润，并加重了 HCC 的进展。SLFN11 敲低的 HCC 细胞通过 C-C 基序趋化因子配体 2 依赖性方式促进巨噬细胞迁移和 M2 样极化，进而通过激活核因子-κB 通路上调自身 PD-L1 表达。在机制上，SLFN11 通过与三结构域蛋白 21 竞争结合 RNA 识别基序 2 结构域的 RNA 结合蛋白 10 来抑制 Notch 通路和 C-C 基序趋化因子配体 2 的转录，从而抑制三结构域蛋白 21 介导的 RNA 结合蛋白 10 降解，稳定 RNA 结合蛋白 10，并促进 NUMB 外显子 9 跳跃。C-C 基序趋化因子受体 2 的药理学拮抗作用增强了 SLFN11 敲低肿瘤荷人源化小鼠中抗 PD-1 的抗肿瘤作用。在 HCC 患者中，血清 SLFN11 水平较高的患者对 ICI 的反应更好。
结论
SLFN11 是微环境免疫特性的关键调节因子，也是 HCC 对 ICI 反应的有效预测生物标志物。阻断 C-C 基序趋化因子配体 2/C-C 基序趋化因子受体 2 信号通路可使 SLFN11 HCC 患者对 ICI 治疗敏感。
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