Single-Cell and Spatial Transcriptomics Link Malignant T Cells to Macrophages in the Tumor Immune Microenvironment of Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma

Introduction: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare and highly aggressive disease that most reported in Asia. However, the specific mechanisms and factors within the tumor microenvironment (TME) that drive this malignant disease remain largely unknown. In this study, we performed a comprehensive analysis of TME in patients with MEITL by single-cell RNA sequencing and spatial transcriptomic, which might help further elucidate the tumor biology and gain an insight to treatments beyond chemotherapy and transplantation.

Methods: A retrospective analysis of the clinical features and pathological data of 20 patients with MEITL treated at the First Affiliated Hospital of Zhejiang University School of Medicine from January 2019 to October 2023 was conducted. Four samples from 4 representative patients were subjected to single-cell RNA sequencing and spatial transcriptomic analysis.

Results: Among the 20 patients with MEITL, there were 13 males and 7 females, with a median age of 55.2 (16-75) years. Nineteen cases (19/20) had lesions located in the jejunum or ileum. Abdominal pain, diarrhea, and fatigue were the main clinical symptoms, with intestinal perforation as the main complication. Immunohistochemistry results showed that most monomorphic epitheliotropic intestinal T-cell lymphoma tumor cells were positive for CD3 (20/20), CD8 (17/20), and CD56 (19/20) expression, while negative for CD5 (19/20) and EBER (18/20) expression. 17 patients died during follow-up due to disesae progression or infection secondary to interstital disease. The estimated one-year OS were 10%. Analysis of single-cell and spatial transcriptomic data revealed that various cells, including MEITL tumor cells, intestinal epithelial cells, and macrophages, were distributed in the intestinal pathological tissue. NK cells were absent among TEM of MEITL. The tumor cells maintain the phenotypes of both T and NK cells. There was a high degree of spatial correlation between tumor cells and macrophages. Further differential gene enrichment analysis of macrophages revealed a positive spatial correlation between tumor cells and M1 macrophages, while the numbers of M1 macrophages under high power field were also related to patients' survival.

Conclusions: Monomorphic epitheliotropic intestinal T-cell lymphoma has an insidious onset, often presenting with acute abdomen, and has a very poor prognosis. According to single-cell sequencing and spatial transcriptomic results, the TME of MEITL is complex with various cells while in absence of NK cells. The high spatial correlation between tumor cells and macrophages suggests the underlying interactions of these two cells during the pathogenesis of MEITL.

No relevant conflicts of interest to declare.