Edwin. L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA.
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Hepatology. 2020 Apr;71(4):1247-1261. doi: 10.1002/hep.30889. Epub 2019 Oct 14.
Activation of the antitumor immune response using programmed death receptor-1 (PD-1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD-1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown.
We recapitulated these clinical outcomes using orthotopic-grafted or induced-murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR-2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8-positive (CD8 ) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor-associated macrophages and reducing T regulatory cell (Treg) and chemokine (C-C motif) receptor 2-positive monocyte infiltration in HCC tissue. In these models, VEGFR-2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD-ligand 1 expression in HCC cells was induced in a paracrine manner upon anti-VEGFR-2 blockade in endothelial cells in part through interferon-gamma expression. Moreover, we found that VEGFR-2 blockade increased PD-1 expression in tumor-infiltrating CD4 cells. We also found that under anti-PD-1 therapy, CD4 cells promote normalized vessel formation in the face of antiangiogenic therapy with anti-VEGFR-2 antibody.
We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti-PD-1 therapy-resistant and anti-PD-1 therapy-responsive HCC models.
使用程序性死亡受体-1（PD-1）阻断来激活抗肿瘤免疫反应仅在一部分肝细胞癌（HCC）患者中显示出获益。将 PD-1 阻断与抗血管生成联合使用已显示出显著增加对治疗有反应的 HCC 患者比例的潜力，但这种相互作用的机制尚不清楚。
我们使用 HCC 的原位移植或诱导的小鼠模型重现了这些临床结果。使用鼠抗血管内皮受体 2（VEGFR-2）的特异性阻断显著延迟了原发性肿瘤的生长，但未能延长生存期，而单独使用抗 PD-1 抗体在一种模型中仅赋予较小的生存优势。然而，双重抗 PD-1/VEGFR-2 治疗在两种模型中均显著抑制了原发性肿瘤的生长并使生存期翻倍。联合治疗通过增加 CD8 阳性（CD8）细胞毒性 T 细胞浸润和激活，改变肿瘤相关巨噬细胞的 M1/M2 比值以及减少 HCC 组织中的 T 调节细胞（Treg）和趋化因子（C-C 基序）受体 2 阳性单核细胞浸润，重新编程了免疫微环境。在这些模型中，VEGFR-2 选择性地在肿瘤内皮细胞中表达。使用 HCC 组织的球体培养物，我们发现 PD-1 配体 1 在 HCC 细胞中的表达在血管内皮细胞中抗 VEGFR-2 阻断后通过干扰素-γ表达以旁分泌方式诱导。此外，我们发现 VEGFR-2 阻断增加了肿瘤浸润性 CD4 细胞中的 PD-1 表达。我们还发现，在抗 PD-1 治疗下，CD4 细胞在抗血管生成治疗中促进了抗 VEGFR-2 抗体的正常化血管形成。
我们表明，双重抗 PD-1/VEGFR-2 治疗在 HCC 中有持久的血管强化作用，可以克服单独治疗的治疗抵抗，并增加对 PD-1 治疗有抵抗和对 PD-1 治疗有反应的 HCC 模型的总生存期。
