Department of Molecular and Cell Biology, Immunotherapy and Vaccine Research Initiative, Cancer Research Laboratory, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, California, USA.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
J Clin Invest. 2018 Oct 1;128(10):4654-4668. doi: 10.1172/JCI99317. Epub 2018 Sep 10.
Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.
检查点阻断免疫疗法针对 PD-1/PD-L1 抑制轴在治疗几种类型的癌症方面取得了显著的效果。虽然细胞毒性 T 细胞在检查点阻断期间被认为提供了重要的抗肿瘤作用，但某些 MHC 表达低的癌症对治疗有反应，这表明其他免疫细胞类型也可能发挥作用。在这里，我们使用了几种癌症小鼠模型来研究 PD-1/PD-L1 阻断对 NK 细胞的影响，NK 细胞是一种具有细胞毒性的先天淋巴细胞，也介导抗肿瘤免疫。我们发现 PD-1/PD-L1 阻断引发了强烈的 NK 细胞反应，这对于免疫治疗的完全治疗效果是必不可少的。PD-1 在可移植的、自发的和遗传诱导的小鼠肿瘤模型中的 NK 细胞上表达，而癌细胞中的 PD-L1 表达导致 NK 细胞反应降低，并在体内产生更具侵袭性的肿瘤。PD-1 在具有激活和更响应表型的 NK 细胞上表达更丰富，并且不标记具有耗竭表型的 NK 细胞。这些结果表明 PD-1/PD-L1 轴在体内抑制 NK 细胞反应的重要性，并揭示 NK 细胞与 T 细胞一起介导 PD-1/PD-L1 阻断免疫治疗的效果。
