High levels of ecto-5′-nucleotidase (CD73) have been implicated in immune suppression and tumor progression, and have also been observed in cancer patients who progress on anti–PD-1 immunotherapy. Although regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known about CD73 expression in other immune cell populations. We found that tumor-infiltrating NK cells upregulate CD73 expression and the frequency of these CD73-positive NK cells correlated with larger tumor size in breast cancer patients. In addition, the expression of multiple alternative immune checkpoint receptors including LAG-3, VISTA, PD-1, and PD-L1 was significantly higher in CD73-positive NK cells than in CD73-negative NK cells. Mechanistically, NK cells transport CD73 in intracellular vesicles to the cell surface and the extracellular space via actin polymerization–dependent exocytosis upon engagement of 4-1BBL on tumor cells. These CD73-positive NK cells undergo transcriptional reprogramming and upregulate IL-10 production via STAT3 transcriptional activity, suppressing CD4-positive T cell proliferation and IFN-γ production. Taken together, our results support the notion that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immunoregulatory properties within the tumor microenvironment.

中文翻译：

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CD73免疫检查点在肿瘤微环境中定义调节性NK细胞

高水平的ecto-5'-核苷酸酶（CD73）与免疫抑制和肿瘤进展有关，在抗PD-1免疫治疗进展的癌症患者中也观察到。尽管调节性T细胞可以通过产生腺苷表达CD73并抑制T细胞反应，但对CD73在其他免疫细胞群体中的表达了解较少。我们发现，浸润肿瘤的NK细胞上调CD73表达，而这些CD73阳性NK细胞的频率与乳腺癌患者的较大肿瘤大小相关。此外，CD73阳性NK细胞中多种替代性免疫检查点受体（包括LAG-3，VISTA，PD-1和PD-L1）的表达明显高于CD73阴性NK细胞。机械上，当4-1BBL与肿瘤细胞结合时，NK细胞通过肌动蛋白聚合依赖性胞吐作用将细胞内小泡中的CD73转运至细胞表面和细胞外空间。这些CD73阳性NK细胞通过STAT3转录活性进行转录重编程并上调IL-10的产生，从而抑制CD4阳性T细胞的增殖和IFN-γ的产生。综上所述，我们的结果支持以下观点：肿瘤可以劫持NK细胞以逃避免疫，并且CD73表达定义了可诱导的NK细胞群体，在肿瘤微环境中具有免疫调节特性。这些CD73阳性NK细胞通过STAT3转录活性进行转录重编程并上调IL-10的产生，从而抑制CD4阳性T细胞的增殖和IFN-γ的产生。综上所述，我们的结果支持以下观点：肿瘤可以劫持NK细胞以逃避免疫，并且CD73表达定义了可诱导的NK细胞群体，在肿瘤微环境中具有免疫调节特性。这些CD73阳性NK细胞通过STAT3转录活性进行转录重编程并上调IL-10的产生，从而抑制CD4阳性T细胞的增殖和IFN-γ的产生。综上所述，我们的结果支持以下观点：肿瘤可以劫持NK细胞以逃避免疫，并且CD73表达定义了可诱导的NK细胞群体，在肿瘤微环境中具有免疫调节特性。