Effective low-dose Anlotinib induces long-term tumor vascular normalization and improves anti-PD-1 therapy.
Effective low-dose Anlotinib induces long-term tumor vascular normalization and improves anti-PD-1 therapy.
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DOI：
10.3389/fimmu.2022.937924
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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安洛替尼是一种新型的多靶点酪氨酸激酶抑制剂，单药治疗具有良好的临床疗效。然而，将Anlotinib和免疫检查点疗法结合以实现最佳抗肿瘤效果同时限制副作用的过程仍不清楚。在这项研究中，我们发现有效的低剂量Anlotinib足以抑制肿瘤生长，同时与高剂量相比减少副作用。有效的低剂量Anlotinib治疗在短期和长期治疗方案中诱导持久的肿瘤血管正常化和改善抗PD-1治疗。从机制上讲，联合治疗增加了肿瘤内CD 4 + T、CD 8 + T和NK细胞的比例。安洛替尼相关的抗肿瘤作用不依赖于干扰素γ;然而，联合治疗需要CD 8 + T细胞来抑制肿瘤生长。总之，这些结果表明，有效的低剂量Anlotinib和PD-1阻断剂的组合诱导了持久的抗肿瘤作用，副作用较少。我们的研究结果表明，抗血管生成治疗与免疫检查点治疗相结合，有效的低剂量，而不是可耐受的高剂量，将更有效，更安全。
Anlotinib is a new multitarget tyrosine kinase inhibitor for tumor angiogenesis, and its monotherapy exhibits a decent clinical efficacy. However, the process of combining Anlotinib and immune checkpoint therapy to achieve optimal antitumor effects while limiting side effects remains unclear. In this study, we found that effective low-dose Anlotinib was sufficient to inhibit tumor growth while reducing side effects compared with high doses. Effective low-dose Anlotinib treatments induced durable tumor vascular normalization and improved anti-PD-1 therapy in both short- and long-term treatment regimens. Mechanistically, the combination therapy increased the proportions of intratumoral CD4+ T, CD8+ T, and NK cells. Anlotinib-associated antitumor effects were independent of interferon γ; however, the combination therapy required CD8+ T cells to suppress tumor growth. Together, these results suggest that the combination of effective low-dose Anlotinib and PD-1 blockade induces durable antitumor effects with fewer side effects. Our findings indicate that antiangiogenic treatments combined with immune checkpoint therapy at an effective low-dose, rather than a tolerable high dose, would be more efficacious and safer.
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