Programmed cell death-1 receptor mediated regulation of Tbet + NK1.1 - Innate Lymphoid Cells within the Tumor Microenvironment
Programmed cell death-1 receptor mediated regulation of Tbet + NK1.1 - Innate Lymphoid Cells within the Tumor Microenvironment
复制标题
程序性细胞死亡 1 受体介导的 Tbet NK1.1 调节 - 肿瘤微环境中的先天淋巴细胞
DOI：
10.1101/2022.09.21.507469
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Lim J
中科院分区：
文献类型：
--
作者：
Lim J
先天性淋巴样细胞（inate lymphoid cells，ILC）在组织免疫中起重要作用，并受辅助受体信号的调控。在这里，我们定义了Tbet+NK1.1−的ILC子集，并且存在于肿瘤微环境（TME）中。我们发现TME内ILC上的程序性死亡-1受体（PD-1）表达见于Tbet+NK1.1− ILC。PD-1在多种小鼠和人类肿瘤中显著控制Tbet+NK1.1− ILC的增殖和功能。我们发现肿瘤来源的乳酸盐增强了TME内Tbet+NK1.1− ILC上的PD-1表达，这导致抑制了哺乳动物雷帕霉素靶蛋白（mTOR）信号传导，沿着脂肪酸摄取增加。与这些代谢变化一致，PD-1缺陷型Tbet+NK1.1− ILC表达的IFNγ和颗粒酶B和K显著增加。此外，PD-1缺陷型Tbet+NK1.1− ILC有助于减少黑色素瘤实验小鼠模型中的肿瘤生长。这些数据表明，PD-1可以调节TME内Tbet+NK1.1− ILC的抗肿瘤反应。
Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are Tbet+NK1.1−and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet+NK1.1−ILCs. PD-1 significantly controlled the proliferation and function of Tbet+NK1.1−ILCs in multiple murine and human tumors. We found tumor-derived lactate enhanced PD-1 expression on Tbet+NK1.1−ILCs within the TME, which resulted in dampened the mammalian target of rapamycin (mTOR) signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1-deficient Tbet+NK1.1−ILCs expressed significantly increased IFNγ and granzyme B and K. Furthermore, PD-1-deficient Tbet+NK1.1−ILCs contributed toward diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate antitumor responses of Tbet+NK1.1−ILCs within the TME.