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Journal of Translational Medicine

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Open Access 01-12-2022 | Lymphoma | Research

Lkb1 aggravates diffuse large B-cell lymphoma by promoting the function of Treg cells and immune escape

Authors: Xiuhua Su, Tao Sun, Meng Li, Yuan Xia, Mingying Li, Dongmei Wang, Fei Lu, Jingjing Ye, Chunyan Ji

Published in: Journal of Translational Medicine | Issue 1/2022

Abstract

Background

Regulatory T cells (Tregs) induce immune responses and may contribute to immune escape in tumors. Accumulation of Tregs in tumors represents a critical barrier to anti-tumor immunity and immunotherapy. However, conflicting results describing the role of Tregs in lymphoma warrant further investigation. The precise features and mechanisms underlying the alteration in Tregs in diffuse large B-cell lymphoma (DLBCL) are not well understood yet. In this study, we analyzed the mechanism underlying the observed alterations in Tregs in DLBCL and examined the effect of Lkb1 expression on the immunosuppressive function of human Tregs.

Methods

Flow cytometry and immunofluorescence were used to analyze the proportion of Tregs and effector Tregs in the peripheral blood and lymph nodes of patients with DLBCL and control group. In vitro culture assays were used to analyze the immunosuppressive function of Tregs in the two groups. Transcriptome sequencing was performed to analyze the differentially expressed genes in the two groups, and the transcription level and protein expression of Lkb1 in the two groups were detected using RT-PCR and WES microprotein technology. Lentiviral vectors were constructed to explore the functional changes of Tregs with stable upregulation and downregulation of Lkb1. Finally, a humanized murine lymphoma model was established to study the function of Lkb1 in Tregs in the pathogenesis of DLBCL.

Results

The number of Tregs was found to be dramatically increased in peripheral blood and tumor tissue in DLBCL patients compared with that in healthy controls, and decreased after treatment. Tregs from DLBCL patients exhibited multiple enhanced functions, including increased inhibition of CD8⁺cytotoxic T cells (CTL) against tumor cells, enhanced suppression of CD8⁺CTL secretion of granular enzyme, and suppression of CD8⁺CTL degranulation. Lkb1 was found to be upregulated in Tregs of DLBCL patients. Furthermore, Lkb1 contributes to Treg immunosuppressive function in DLBCL by regulating the mevalonate pathway. Finally, deletion of Lkb1 in Tregs suppressed tumor growth and promoted anti-tumor immunity in a DLBCL murine model.

Conclusions

These findings confirmed that Lkb1-regulated Tregs are critical for immune escape in DLBCL, which emphasizes that Lkb1 is a potential target for the immunotherapy of DLBCL.

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Title: Lkb1 aggravates diffuse large B-cell lymphoma by promoting the function of Treg cells and immune escape
Authors: Xiuhua Su
Tao Sun
Meng Li
Yuan Xia
Mingying Li
Dongmei Wang
Fei Lu
Jingjing Ye
Chunyan Ji
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Lymphoma
Diffuse Large B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma
Published in: Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-022-03588-0

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