Low-Dose Anti-Angiogenic Therapy Sensitizes Breast Cancer to PD-1 Blockade
Low-Dose Anti-Angiogenic Therapy Sensitizes Breast Cancer to PD-1 Blockade
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DOI：
10.1158/1078-0432.ccr-19-2179
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发表时间：
2020-04-01
影响因子：
11.5
通讯作者：
Liu, Jieqiong
中科院分区：
文献类型：
--
作者：
Li, Qian;Wang, Yifan;Liu, Jieqiong
尽管取得了巨大的成功，但癌症免疫治疗的总体反应率仍然不理想，特别是在乳腺癌中。将免疫检查点抑制剂与靶向药物组合以增强抗肿瘤作用的兴趣增加。抗血管生成药物已被证明与免疫检查点阻断协同作用，但结合这两种模式和协同反应的潜在机制的最佳设置尚未完全understood.Experimental Design：我们测试了抗PD-1和不同剂量的VEGFR 2靶向药物在同基因乳腺癌小鼠模型中的组合。通过流式细胞术分析肿瘤浸润的免疫细胞亚群。进行细胞因子阵列以鉴定不同治疗条件下的炎症变化。在晚期三阴性乳腺癌（TNBC）患者中进一步评估联合抗血管生成和抗PD-1治疗的疗效。结果：阻断VEGFR 2以剂量依赖性方式使乳腺肿瘤对PD-1阻断敏感。尽管常规和低剂量抗VEGFR 2抗体治疗均使肿瘤血管正常化，但低剂量VEGFR 2阻断导致更强的免疫细胞浸润和激活，并促进CD 8（+）T细胞分泌骨桥蛋白（OPN）。OPN随后诱导肿瘤细胞产生TGF-β，这反过来又上调免疫细胞上的PD-1表达。在晚期TNBC患者中，低剂量抗VEGFR 2抑制剂和抗PD-1联合治疗显示出极佳的耐受性和疗效。更高的OPN和TGF-β表达与改善treatment respons.Conclusions：总之，这些结果表明，抗血管生成治疗和免疫检查点阻断之间的剂量依赖性协同作用，从而提供了重要的见解，结合免疫治疗与分子靶向药物的最佳策略。
Purpose: Despite its enormous successes, the overall response rate of cancer immunotherapy remains suboptimal, especially in breast cancer. There is an increased interest in combining immune checkpoint inhibitor with targeted agents to enhance antitumor effect. Anti-angiogenic drugs have been shown to synergize with immune checkpoint blockades, but the optimal setting for combining these two modalities and the underlying mechanisms of synergistic responses are not fully understood.Experimental Design: We tested the combination of anti-PD-1 and different doses of VEGFR2-targeting agents in syngeneic breast cancer mouse models. Tumor-infiltrated immune cell subsets were profiled by flow cytometry. A cytokine array was carried out to identify inflammatory changes in different treatment conditions. The efficacy of combined anti-angiogenic and anti-PD-1 therapy was further evaluated in patients with advanced triple-negative breast cancer (TNBC).Results: Blockade of VEGFR2 sensitizes breast tumors to PD-1 blockade in a dose-dependent manner. Although both conventional and low-dose anti-VEGFR2 antibody treatments normalize tumor vessels, low-dose VEGFR2 blockade results in more robust immune cell infiltration and activation and promotes the secretion of osteopontin (OPN) byCD8(+) T cells. OPN subsequently induces tumor cell production of TGF-beta, which in turn upregulates PD-1 expression on immune cells. In patients with advanced TNBC, combined treatment with low-dose anti-VEGFR2 inhibitor and anti-PD-1 demonstrated excellent tolerability and efficacy. Higher OPN and TGF-b expressions correlated with improved treatment responses.Conclusions: Together, these results demonstrate a dose-dependent synergism between anti-angiogenic therapy and immune checkpoint blockade, thus providing important insights into the optimal strategies for combining immunotherapy with molecular-targeted agents.