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 non-responsive advanced HCC patients identified SLAMF7 upregulation in immunotherapy-responsive HCC, and HCC patients 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.

中文翻译：

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通过靶向 SLAMF7 调节的 CCL2 信号使免疫抑制巨噬细胞复极化使肝细胞癌对免疫治疗敏感

免疫检查点抑制剂对肝细胞癌（HCC）的疗效有限。巨噬细胞是肝癌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可能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) 家族成员调节各种免疫功能，我们研究了特定 SLAM 受体在 HCC 免疫生物学中的作用。比较免疫治疗有反应和无反应的晚期 HCC 患者的转录组图谱发现，免疫治疗有反应的 HCC 中 SLAMF7 上调，并且对免疫治疗有反应的 HCC 患者也表现出较高的血清 SLAMF7 水平。肝脏特异性基因敲除小鼠中 Slamf7 的缺失导致肝癌发生和转移增加、免疫抑制巨噬细胞浸润增加以及 CD8+ T 细胞中 PD-1 表达上调。HCC 细胞固有的 SLAMF7 抑制 MAPK/ATF2 介导的 CCL2 表达，从而调节体外巨噬细胞迁移和极化。从机制上讲，SLAMF7 通过其细胞质 304 酪氨酸位点与包含 SH2 结构域的接头蛋白 B (SHB) 结合，促进 SHIP1 招募到 SLAMF7 并抑制 TRAF6 的泛素化，从而减弱 MAPK 通路激活和 CCL2 转录。CCL2/CCR2 轴的药理学拮抗作用增强了抗 PD-1 抗体在 SLAMF7 低表达的原位 HCC 小鼠模型中的治疗效果。总之，本研究强调 SLAMF7 作为巨噬细胞功能的调节剂和 HCC 免疫治疗反应的潜在预测生物标志物。在 SLAMF7 水平较低的 HCC 中，针对 CCL2 信号传导诱导巨噬细胞复极化的策略可能会增强免疫治疗的疗效。