Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands.
Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands.
Cancer Cell. 2020 Nov 9;38(5):685-700.e8. doi: 10.1016/j.ccell.2020.09.001. Epub 2020 Oct 1.
PD-1/PD-L1-checkpoint blockade therapy is generally thought to relieve tumor cell-mediated suppression in the tumor microenvironment but PD-L1 is also expressed on non-tumor macrophages and conventional dendritic cells (cDCs). Here we show in mouse tumor models that tumor-draining lymph nodes (TDLNs) are enriched for tumor-specific PD-1 T cells which closely associate with PD-L1 cDCs. TDLN-targeted PD-L1-blockade induces enhanced anti-tumor T cell immunity by seeding the tumor site with progenitor-exhausted T cells, resulting in improved tumor control. Moreover, we show that abundant PD-1/PD-L1-interactions in TDLNs of nonmetastatic melanoma patients, but not those in corresponding tumors, associate with early distant disease recurrence. These findings point at a critical role for PD-L1 expression in TDLNs in governing systemic anti-tumor immunity, identifying high-risk patient groups amendable to adjuvant PD-1/PD-L1-blockade therapy.
PD-1/PD-L1 检查点阻断疗法通常被认为可以缓解肿瘤微环境中肿瘤细胞介导的抑制作用，但 PD-L1 也在非肿瘤巨噬细胞和常规树突状细胞（cDCs）上表达。在这里，我们在小鼠肿瘤模型中表明，引流肿瘤的淋巴结（TDLNs）富含与 PD-L1 cDCs 密切相关的肿瘤特异性 PD-1 T 细胞。TDLN 靶向 PD-L1 阻断通过将祖细胞耗竭的 T 细胞播种到肿瘤部位，诱导增强的抗肿瘤 T 细胞免疫，从而改善肿瘤控制。此外，我们表明，非转移性黑色素瘤患者 TDLNs 中丰富的 PD-1/PD-L1 相互作用，但与其相应肿瘤中的 PD-1/PD-L1 相互作用不同，与早期远处疾病复发相关。这些发现表明 PD-L1 在 TDLNs 中的表达在控制全身抗肿瘤免疫方面起着关键作用，确定了对辅助性 PD-1/PD-L1 阻断治疗有反应的高危患者群体。
