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. Here, we employed 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 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 (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 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. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.

中文翻译：

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ACE2 通过抑制巨噬细胞诱导的免疫抑制和血管生成增强对 PD-L1 阻断的敏感性


基于抗 PD-L1 的联合免疫疗法已成为不可切除肝细胞癌 （HCC） 的一线治疗。然而，客观缓解率低于 40%，突出表明需要确定对免疫检查点抑制剂的耐受性机制和准确的反应生物标志物。在这里，我们采用下一代测序来分析 10 名接受抗 PD-L1 治疗的患者的 HCC 样本。与反应者相比，无反应者肾素-血管紧张素系统的激活升高，无反应者 ACE2 表达显着下调。ACE2 缺陷促进 HCC 发展和抗 PD-L1 耐药，而 ACE2 过表达抑制免疫功能正常小鼠的 HCC 进展。飞行时间质谱流式细胞术 （CyTOF） 显示，ACE2 缺陷小鼠原位肿瘤组织具有升高的 M2 样肿瘤相关巨噬细胞 （TAM），表现出 CCR5+PD-L1+ 免疫抑制表型，并表现出高 VEGFα 表达。ACE2 通过抑制 ACE2/血管紧张素-（1-7）/Mas 受体轴的 NF-κB 信号传导，下调肿瘤内源性 CCL5 表达。较低的 CCL5 水平导致 JAK-STAT3 通路的激活减少，并抑制巨噬细胞中 PD-L1 和 VEGFα 的表达，阻断巨噬细胞浸润和 M2 样极化。使用 maraviroc 对 CCR5 的药理学靶向增强了抗 PD-L1 治疗的肿瘤抑制作用。总之，这些发现表明 ACE2 轴的激活克服了 HCC 的免疫抑制微环境，并可能作为免疫治疗靶点和对 PD-L1 阻断反应的预测生物标志物。