Single‐Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T‐Cell Lymphoma

• Published in: Advanced science 2023-12, Vol.10 (36), p.e2303913-n/a
• Main Authors: Li, Yi‐Qi, Luo, Chun‐Ling, Jiang, Jia‐Xin, He, Shuai, Liu, Yang, Yan, Wen‐Xin, Xia, Yi, Cui, Qian, Huang, Ying, Lim, Jing Quan, Huang, Dachuan, Hussein, Izzah Nabilah, Gao, Yan, Lin, Guo‐Wang, Ling, Yi‐Hong, Ma, Dong, Zhang, Yue‐Tong, Chan, Jason Yongsheng, Wei, Pan‐Pan, Wang, Xiao‐Xiao, Cheng, Chee Leong, Xiong, Jie, Zhao, Wei‐Li, Ong, Choon Kiat, Lim, Soon Thye, Huang, Hui‐Qiang, Peng, Rou‐Jun, Bei, Jin‐Xin
• Format: Article
• Language: English
• Subjects: Cancer; Cell cycle; DPP4; Epstein-Barr virus; Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - pathology; Herpesvirus 4, Human - genetics; Humans; immunosuppression; LMP1+ malignant NK cells; Lymphoma; Lymphoma, Extranodal NK-T-Cell - genetics; Lymphoma, Extranodal NK-T-Cell - pathology; Mutation; NKTCL; Prognosis; scRNA‐seq; Single-Cell Analysis; Tumor Microenvironment; Tumors
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202303913

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. Single‐cell RNA‐sequencing analysis and functional investigations uncover the pivotal role of EBV, particularly the viral gene LMP1, in the malignant transformation and progression of NKTCL. Malignant NK cells entertain with immune cells to jointly foster an immunosuppressive TME favorable for NKTCL development. Targeting TME components, including LMP1 and DPP4, emerges as a potential therapeutic strategy against NKTCL.