Lenvatinib enhances T cell immunity and the efficacy of adoptive chimeric antigen receptor-modified T cells by decreasing myeloid-derived suppressor cells in cancer
Lenvatinib enhances T cell immunity and the efficacy of adoptive chimeric antigen receptor-modified T cells by decreasing myeloid-derived suppressor cells in cancer
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乐伐替尼通过减少癌症中骨髓源性抑制细胞来增强 T 细胞免疫和过继嵌合抗原受体修饰 T 细胞的功效
DOI：
10.1016/j.phrs.2061.105829
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发表时间：
2021-12-01
影响因子：
9.3
通讯作者：
Zhang, Qing
中科院分区：
文献类型：
--
作者：
Lu, Mengmeng;Zhang, Xiaokang;Zhang, Qing
背景：乐伐替尼是一种酪氨酸激酶抑制剂，已被批准用于治疗多种癌症。但其对T细胞抗肿瘤免疫的调节活性及相关机制有待进一步研究。方法：比较乐伐替尼在免疫功能正常和免疫缺陷小鼠中的抗肿瘤活性，以确定T细胞免疫的作用。通过细胞因子的产生和过继性 T 细胞治疗来分析 T 细胞的抗肿瘤活性。通过检测与MDSCs共培养后T细胞中细胞因子的产生来确定MDSCs对T细胞的免疫抑制作用。通过在小鼠肾癌模型中与靶向碳酸酐酶 IX (CAIX) 的 CAR-T 细胞联合治疗来确定乐伐替尼的辅助免疫治疗效果。结果：乐伐替尼在免疫功能正常小鼠中的抗肿瘤活性高于免疫缺陷小鼠，并且通过 CD8+T 细胞耗竭而减弱。乐伐替尼增加 T 细胞的增殖、肿瘤浸润和抗肿瘤活性。重要的是，乐伐替尼处理的 T 细胞的过继转移在体内表现出长期的抗肿瘤反应。从机制上讲，仑伐替尼上调肿瘤中 T 细胞相关趋化因子（CXCL10 和 CCL8），并降低 MDSC 的频率和免疫抑制活性。此外，乐伐替尼增强了小鼠肾癌模型中 CAR-T 细胞的功效。结论：我们的研究揭示了乐伐替尼通过增强 T 细胞介导的抗肿瘤免疫的新抗肿瘤机制。这些发现对于指导乐伐替尼的临床使用具有重要意义，并为未来与T细胞疗法或其他免疫疗法的联合治疗提供了良好的候选者。
Background: Lenvatinib, a tyrosine kinase inhibitor, has been approved for the treatment of several cancers. However, its regulatory activity and related mechanisms on T cell antitumour immunity need to be further investigated.Methods: The antitumour activity of lenvatinib in immunocompetent and immunodeficient mice was compared to determine the role of T cell immunity. The antitumour activity of T cells was analysed by cytokine production and adoptive T cell therapy. The immunosuppressive effects of MDSCs on T cells were determined by detecting cytokine production in T cells after being cocultured with MDSCs. The adjuvant immunotherapy effect of lenvatinib was determined by combination therapy with CAR-T cells targeted carbonic anhydrase IX (CAIX) in a murine renal cancer model.Results: The antitumour activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+T cell depletion. Lenvatinib increased proliferation, tumour infiltration and antitumour activity of T cells. Importantly, adoptive transfer of lenvatinib-treated T cells showed a long-term antitumour response in vivo. Mechanistically, lenvatinib upregulated T cell-related chemokines (CXCL10 and CCL8) in tumours and decreased the frequency and immunosuppressive activity of MDSCs. Furthermore, lenvatinib enhanced the efficacy of CAR-T cells in a murine renal cancer model.Conclusion: Our study revealed novel antitumour mechanisms of lenvatinib by enhancing T cell-mediated antitumour immunity. These findings are of great significance for guiding the clinical use of lenvatinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies.