ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis

作者：Peiyi Xie, Lei Guo, Qiang Yu, Yufei Zhao, Mincheng Yu, Hui Wang, Mengyuan Wu, Wenxin Xu, Min Xu, Xiao‐Dong Zhu, Yongfeng Xu, Yong-Sheng Xiao, Cheng Huang, Jian Zhou, Jia Fan, Mien‐Chie Hung, Hui‐Chuan Sun, Qing‐Hai Ye, Bo Zhang, Hui Li · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/0008-5472.can-24-0954 · 被引用次数：33 · 研究领域：Ferroptosis and cancer prognosis、Cancer Mechanisms and Therapy、Cancer Immunotherapy and Biomarkers

Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. In this study, we used next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and angiotensin-converting enzyme 2 (ACE2) expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune-competent mice. Mass cytometry by time of flight revealed that ACE2-deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages, displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor-intrinsic chemokine (C-C motif) ligand 5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1-7)/Mas receptor axis. The lower chemokine (C-C motif) ligand 5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacologic targeting of CCR5 using maraviroc enhanced the tumor-suppressive effect of anti-PD-L1 ...