单细胞分析揭示恶性细胞重塑细胞景观并培育结外 NK/T 细胞淋巴瘤的免疫抑制微环境。
Single-Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T-Cell Lymphoma.
发表日期：2023 Nov 10
作者：
Yi-Qi Li, Chun-Ling Luo, Jia-Xin Jiang, Shuai He, Yang Liu, Wen-Xin Yan, Yi Xia, Qian Cui, Ying Huang, Jing Quan Lim, Dachuan Huang, Izzah Nabilah Hussein, Yan Gao, Guo-Wang Lin, Yi-Hong Ling, Dong Ma, Yue-Tong Zhang, Jason Yongsheng Chan, Pan-Pan Wei, Xiao-Xiao Wang, Chee Leong Cheng, Jie Xiong, Wei-Li Zhao, Choon Kiat Ong, Soon Thye Lim, Hui-Qiang Huang, Rou-Jun Peng, Jin-Xin Bei
来源：
Stem Cell Research & Therapy
摘要：
结外自然杀伤/T 细胞淋巴瘤 (NKTCL) 是一种与 Epstein-Barr 病毒 (EBV) 相关的侵袭性淋巴瘤，其特点是肿瘤行为异质性。为了更好地了解异质性的起源，本研究利用单细胞 RNA 测序 (scRNA-seq) 分析在单细胞水平上分析 NKTCL 的肿瘤微环境 (TME)。结合体外和体内模型，该研究确定了 LMP1 恶性 NK 细胞的子集，其有助于 NKTCL 中异质性恶性细胞的肿瘤发生和发展。此外，恶性NK细胞通过趋化因子及其受体与多种免疫细胞相互作用，分泌大量DPP4，损害免疫细胞的趋化性并调节其浸润。它们还对 T 细胞表现出免疫抑制作用，LMP1 进一步增强了这种作用。此外，EBV 编码基因的高转录和肿瘤相关巨噬细胞 (TAM) 的低浸润是多个患者队列中 NKTCL 的有利预后指标。这项研究首次在单细胞分辨率下破译了 NKTCL TME 的异质组成，强调了具有 EBV 编码的 LMP1 的恶性 NK 细胞在重塑细胞景观和培育免疫抑制微环境中的关键作用。这些发现为理解 NKTCL 的致病机制和开发针对 NKTCL 的新治疗策略提供了见解。© 2023 作者。 《先进科学》由 Wiley-VCH GmbH 出版。
Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive type of lymphoma associated with Epstein-Barr virus (EBV) and characterized by heterogeneous tumor behaviors. To better understand the origins of the heterogeneity, this study utilizes single-cell RNA sequencing (scRNA-seq) analysis to profile the tumor microenvironment (TME) of NKTCL at the single-cell level. Together with in vitro and in vivo models, the study identifies a subset of LMP1+ malignant NK cells contributing to the tumorigenesis and development of heterogeneous malignant cells in NKTCL. Furthermore, malignant NK cells interact with various immunocytes via chemokines and their receptors, secrete substantial DPP4 that impairs the chemotaxis of immunocytes and regulates their infiltration. They also exhibit an immunosuppressive effect on T cells, which is further boosted by LMP1. Moreover, high transcription of EBV-encoded genes and low infiltration of tumor-associated macrophages (TAMs) are favorable prognostic indicators for NKTCL in multiple patient cohorts. This study for the first time deciphers the heterogeneous composition of NKTCL TME at single-cell resolution, highlighting the crucial role of malignant NK cells with EBV-encoded LMP1 in reshaping the cellular landscape and fostering an immunosuppressive microenvironment. These findings provide insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.