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Single-Cell Transcriptome Analysis Identifies Key Components of Tumor Microenvironment for Extranodal Natural Killer/T-cell lymphoma

ABSTRACT: Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated lymphoma with heterogeneous tumor behaviors and clinical outcomes. Here, we profiled tumor microenvironment (TME) of NKTCL through single-cell transcriptome analysis of 137,304 cells from 10 tumor-blood pairs. We identified six malignant subtypes with diverse transcriptional signatures, among which LMP1+ NK_C9_CXCL13 was characterized with oncogenic and immunosuppressive potentials as well as an axial role in malignant transformation. Moreover, ligand-receptor analyses and multiplex immunofluorescent staining assays revealed intensive interactions among malignant NK, tumoral myeloid, and T cells, fostering immunosuppressive TME in NKTCL. Furthermore, co-culture assays revealed that malignant cells induced the development of immunosuppressive and pro-tumorigenic tumor-associated macrophages (TAMs) through high expression of CSF1 and hampered the recruitment of normal NK cells through broad secretion of a dipeptidylpeptidase DPP4 in NKTCL. Lastly, we revealed the inter-patient heterogeneity of NKTCL with distinct EBV transcription and TAM infiltration in multiple patient cohorts, of which high and low were favorable prognostic indicators for NKTCL patients, respectively. Collectively, for the first time to our knowledge, our study dissects the heterogeneous composition of NKTCL TME at single-cell resolution, which provides insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203663 | GEO | 2024/01/03

REPOSITORIES: GEO

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Project description:Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

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Single-Cell Transcriptome Analysis Identifies Key Components of Tumor Microenvironment for Extranodal Natural Killer/T-cell lymphoma

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