Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy
Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy
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DOI：
10.1172/jci.insight.124507
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发表时间：
2018-12-06
期刊：
影响因子：
8
通讯作者：
Ossendorp, Ferry
中科院分区：
文献类型：
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作者：
Fransen, Marieke F.;Schoonderwoerd, Mark;Ossendorp, Ferry
PD-1/PD-L1检查点治疗癌症通常被认为是通过重新激活肿瘤微环境中的T细胞来发挥作用的。在这里，我们提供了来自2个小鼠肿瘤模型的数据，证明了肿瘤引流淋巴结在PD-1和PD-L1治疗效果中的重要参与。检查点治疗诱导的免疫激活主要在肿瘤引流的淋巴结中观察到，但不是非引流的，并反映在CD8(+)T细胞的局部聚集上。手术切除这些淋巴结，但不切除对侧淋巴结，可以消除治疗诱导的肿瘤消退，并与肿瘤微环境中免疫浸润物的减少有关。此外，将淋巴细胞锁定在淋巴器官中的抑制剂FTY720也废除了检查点治疗，这表明肿瘤引流淋巴结的功能是检查点阻断治疗所需的T细胞激活部位。现在PD-1/PD-L1检查点治疗被应用于癌症的早期临床阶段，我们的临床前数据主张登记肿瘤引流淋巴仍在的患者，以最佳地进行抗肿瘤免疫反应，从而提高临床效益。
PD-1/PD-L1 checkpoint therapy for cancer is commonly considered to act by reactivating T cells in the tumor microenvironment. Here, we present data from 2 mouse tumor models demonstrating an essential involvement of tumor-draining lymph nodes in PD-1 and PD-L1 therapeutic efficacy. Immune activation induced by checkpoint treatment was predominantly observed in the tumor-draining, but not nondraining, lymph nodes and was reflected in local accumulation of CD8(+) T cells. Surgical resection of these lymph nodes, but not contralateral lymph nodes, abolished therapy-induced tumor regressions and was associated with decreased immune infiltrate in the tumor microenvironment. Moreover, inhibitor FTY720, which locks lymphocytes in lymph organs, also abrogated checkpoint therapy, suggesting that the tumor-draining lymph nodes function as sites of T cell invigoration required for checkpoint blockade therapy. Now that PD-1/PD-L1 checkpoint treatment is applied in earlier clinical stages of cancer, our preclinical data advocate for enrolling patients with their tumor-draining lymph nodes still in place, to optimally engage the antitumor immune response and thereby enhance clinical benefit.