Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Inmunología, Buenos Aires, Argentina.
Front Immunol. 2021 Sep 20;12:745939. doi: 10.3389/fimmu.2021.745939. eCollection 2021.
Natural Killer (NK) cells play a key role in cancer immunosurveillance. However, NK cells from cancer patients display an altered phenotype and impaired effector functions. In addition, evidence of a regulatory role for NK cells is emerging in diverse models of viral infection, transplantation, and autoimmunity. Here, we analyzed clear cell renal cell carcinoma (ccRCC) datasets from The Cancer Genome Atlas (TCGA) and observed that a higher expression of NK cell signature genes is associated with reduced survival. Analysis of fresh tumor samples from ccRCC patients unraveled the presence of a high frequency of tumor-infiltrating PD-L1 NK cells, suggesting that these NK cells might exhibit immunoregulatory functions. , PD-L1 expression was induced on NK cells from healthy donors (HD) upon direct tumor cell recognition through NKG2D and was further up-regulated by monocyte-derived IL-18. Moreover, generated PD-L1 NK cells displayed an activated phenotype and enhanced effector functions compared to PD-L1 NK cells, but simultaneously, they directly inhibited CD8 T cell proliferation in a PD-L1-dependent manner. Our results suggest that tumors might drive the development of PD-L1-expressing NK cells that acquire immunoregulatory functions in humans. Hence, rational manipulation of these regulatory cells emerges as a possibility that may lead to improved anti-tumor immunity in cancer patients.
自然杀伤 (NK) 细胞在癌症免疫监视中发挥着关键作用。然而，来自癌症患者的 NK 细胞表现出改变的表型和受损的效应功能。此外，NK 细胞在多种病毒感染、移植和自身免疫模型中具有调节作用的证据正在出现。在这里，我们分析了来自癌症基因组图谱 (TCGA) 的透明细胞肾细胞癌 (ccRCC) 数据集，观察到 NK 细胞特征基因的高表达与生存率降低有关。对 ccRCC 患者的新鲜肿瘤样本进行分析揭示了存在高频率的浸润肿瘤 PD-L1 NK 细胞，表明这些 NK 细胞可能具有免疫调节功能。进一步的研究表明，PD-L1 表达在 NK 细胞上被诱导，当 NK 细胞通过 NKG2D 直接识别肿瘤细胞时，PD-L1 表达被诱导，并且进一步被单核细胞衍生的 IL-18 上调。此外，从健康供体 (HD) 中分离出的 NK 细胞经直接肿瘤细胞识别后通过 NKG2D 表达 PD-L1，并且通过单核细胞衍生的 IL-18 进一步上调。此外，生成的 PD-L1 NK 细胞与 PD-L1 NK 细胞相比，表现出激活的表型和增强的效应功能，但同时，它们以 PD-L1 依赖性方式直接抑制 CD8 T 细胞的增殖。我们的结果表明，肿瘤可能导致表达 PD-L1 的 NK 细胞的发展，这些 NK 细胞在人类中获得免疫调节功能。因此，对这些调节细胞进行合理的操纵可能会导致癌症患者的抗肿瘤免疫增强。
