Weng Jialei, Wang Zheng, Hu Zhiqiu, Xu Wenxin, Sun Jia-Lei, Wang Fu, Zhou Qiang, Liu Shaoqing, Xu Min, Xu Minghao, Gao Dongmei, Shen Ying-Hao, Yi Yong, Shi Yi, Dong Qiongzhu, Zhou Chenhao, Ren Ning
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, P.R. China.
Cancer Res. 2024 Jun 4;84(11):1817-1833. doi: 10.1158/0008-5472.CAN-23-3106.
Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and nonresponsive patients with advanced HCC identified SLAMF7 upregulation in immunotherapy-responsive HCC, and patients with HCC who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy.
CCL2 upregulation caused by SLAMF7 deficiency in hepatocellular carcinoma cells induces immunosuppressive macrophage polarization and confers resistance to immune checkpoint blockade, providing potential biomarkers and targets to improve immunotherapy response in patients.
免疫检查点抑制剂在肝细胞癌（HCC）中的疗效有限。巨噬细胞是HCC中最丰富的免疫细胞，这表明更好地了解肿瘤细胞调节巨噬细胞的内在过程有助于确定改善免疫治疗反应的策略。由于信号淋巴细胞激活分子（SLAM）家族成员调节多种免疫功能，我们研究了特定SLAM受体在HCC免疫生物学中的作用。对晚期HCC免疫治疗反应者和无反应者的转录组图谱进行比较，发现免疫治疗反应性HCC中SLAMF7上调，且对免疫治疗有反应的HCC患者血清中SLAMF7水平也更高。肝脏特异性敲除小鼠中Slamf7的缺失导致肝癌发生和转移增加、免疫抑制性巨噬细胞浸润升高以及CD8+T细胞中PD-1表达上调。HCC细胞内在的SLAMF7抑制MAPK/ATF2介导的CCL2表达，以在体外调节巨噬细胞迁移和极化。机制上，SLAMF7通过其细胞质304酪氨酸位点与含SH2结构域的衔接蛋白B（SHB）结合，促进SHIP1募集到SLAMF7并抑制TRAF6的泛素化，从而减弱MAPK途径激活和CCL2转录。CCL2/CCR2轴的药理学拮抗增强了抗PD-1抗体在SLAMF7表达低的原位HCC小鼠模型中的治疗效果。总之，本研究强调SLAMF7是巨噬细胞功能的调节因子以及HCC免疫治疗反应的潜在预测生物标志物。针对CCL2信号传导以在SLAMF7低的HCC中诱导巨噬细胞重极化的策略可能会提高免疫治疗的疗效。
肝细胞癌细胞中SLAMF7缺乏导致的CCL2上调诱导免疫抑制性巨噬细胞极化并赋予对免疫检查点阻断的抗性，为改善患者免疫治疗反应提供了潜在的生物标志物和靶点。
