journal contribution
posted on 2024-06-04, 07:22 authored by Jialei Weng, Zheng Wang, Zhiqiu Hu, Wenxin Xu, Jia-Lei Sun, Fu Wang, Qiang Zhou, Shaoqing Liu, Min Xu, Minghao Xu, Dongmei Gao, Ying-Hao Shen, Yong Yi, Yi Shi, Qiongzhu Dong, Chenhao Zhou, Ning Ren (A) Immunoblot assay of SHB protein level in the indicated HCC cells. (B-C) Immunoblot assays of phosphorylated and non-phosphorylated SHIP1, and K63-linked ubiquitinated TRAF6 level in the indicated HCC cells with and without SHB silence.
Funding
National Natural Science Foundation of China (NSFC)
Science and Technology Innovation Plan Of Shanghai Science and Technology Commission (上海市科技创新行动计划项目)
China Postdoctoral Science Foundation (China Postdoctoral Foundation Project)
Shanghai Shen Kang Hospital Development Center
Ministry of Education of the People's Republic of China (MOE)
History
ARTICLE ABSTRACT
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.
