Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA; Jiangxi Provincial Children's Hospital, Jiangxi, Nanchang, China.
Cell Metab. 2021 Oct 5;33(10):2040-2058.e10. doi: 10.1016/j.cmet.2021.09.002. Epub 2021 Sep 23.
One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.
前转移龛的定义特征之一，也是原发性肿瘤转移的基本要求，是免疫抑制性巨噬细胞的浸润。这些巨噬细胞如何获得其表型在很大程度上仍未得到探索。在这里，我们证明肿瘤来源的外泌体（TDE）通过 NF-κB 依赖性、糖酵解占主导地位的代谢重编程，将巨噬细胞极化为具有免疫抑制表型的特征，表现为 PD-L1 表达增加。TDE 通过 TLR2 和 NF-κB 信号转导导致葡萄糖摄取增加。TDE 还刺激 NOS2 的升高，这抑制了线粒体氧化磷酸化，导致丙酮酸向乳酸的转化率增加。乳酸反馈作用于 NF-κB，进一步增加 PD-L1。对非小细胞肺癌患者的转移阴性淋巴结进行分析表明，巨噬细胞 PD-L1 与原发性肿瘤中 GLUT-1 和囊泡释放基因 YKT6 的水平呈正相关。总的来说，我们的研究提供了一种新的机制，即前转移龛中的巨噬细胞获得其免疫抑制表型，并确定了外泌体、代谢和转移之间的重要联系。
