Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes.
Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes.
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DOI：
10.1158/2326-6066.cir-16-0385
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发表时间：
2017-06
影响因子：
10.1
通讯作者：
Hodi FS
中科院分区：
文献类型：
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作者：
Wu X;Li J;Connolly EM;Liao X;Ouyang J;Giobbie-Hurder A;Lawrence D;McDermott D;Murphy G;Zhou J;Piesche M;Dranoff G;Rodig S;Shipp M;Hodi FS
在一项 I 期研究中，抗 VEGF 阻断剂（贝伐珠单抗）与免疫检查点抗 CTLA-4 阻断剂（伊匹单抗）的组合显示肿瘤内皮激活和免疫细胞浸润与转移性黑色素瘤患者良好的临床结果相关。为了确定导致这些观察结果的潜在免疫靶标，使用来自长期反应患者的治疗后血浆来筛选人类蛋白质阵列。我们报道，伊匹单抗联合贝伐珠单抗治疗引发了针对半乳糖凝集素-1 (Gal-1) 的体液免疫反应，半乳糖凝集素-1 (Gal-1) 在 37.2% 的治疗患者中表现出促肿瘤、促血管生成和免疫抑制活性。从治疗后血浆中纯化的 Gal-1 抗体可抑制 Gal-1 与 CD45 的结合，CD45 是一种 T 细胞表面受体，在与细胞外 Gal-1 结合后转导细胞凋亡信号。在具有治疗反应的患者组中更频繁地发现对 Gal-1 的抗体反应，并且与总生存期的改善相关。相比之下，接受治疗的另一组患者的循环 Gal-1 蛋白反而增加，并且总体生存率降低。我们的研究结果表明，针对 Gal-1 的体液免疫可能有助于抗 VEGF 和抗 CTLA-4 联合治疗的疗效。 Gal-1 可能提供一个额外的治疗靶点，将抗血管生成和免疫检查点阻断联系起来。
The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti–CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, post-treatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1) which exhibits pro-tumor, pro-angiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from post-treatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti–CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade.