Gastric cancer derived exosomal THBS1 enhanced Vγ9Vδ2 T-cell function through activating RIG-I-like receptor signaling pathway in a N6-methyladenosine methylation dependent manner

Juntao Li; Huang Feng; Jinghan Zhu; Kexi Yang; Guangbo Zhang; Yanzheng Gu; Tongguo Shi; Weichang Chen

doi:10.1016/j.canlet.2023.216410

Gastric cancer derived exosomal THBS1 enhanced Vγ9Vδ2 T-cell function through activating RIG-I-like receptor signaling pathway in a N6-methyladenosine methylation dependent manner

Cancer Lett. 2023 Nov 1:576:216410. doi: 10.1016/j.canlet.2023.216410. Epub 2023 Oct 7.

Authors

Juntao Li¹, Huang Feng², Jinghan Zhu³, Kexi Yang², Guangbo Zhang⁴, Yanzheng Gu⁵, Tongguo Shi⁶, Weichang Chen⁷

Affiliations

¹ Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China; Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
² Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
³ Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
⁴ Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.
⁵ Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China. Electronic address: gyz_1982@yeah.net.
⁶ Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China. Electronic address: shitg@suda.edu.cn.
⁷ Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China; Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: weichangchen@126.com.

PMID: 37783390
DOI: 10.1016/j.canlet.2023.216410

Abstract

Gamma delta (γδ) T-cell-based immunotherapy has shown favorable safety and clinical response in patients with multiple types of cancer. However, its efficiency in treating patients with solid tumors remains limited. In the current study, we investigated the function and molecular mechanism underlying gastric cancer (GC) cell-derived exosomal THBS1 in the regulation of Vγ9Vδ2 T cells. We found that GC cell-derived exosomal THBS1 markedly enhanced the cytotoxicity of Vγ9Vδ2 T cells against GC cells and the production of IFN-γ, TNF-α, perforin and granzyme B in vitro and elevated the killing effects of Vγ9Vδ2 T cells on GC cells in vivo. Mechanistically, exosomal THBS1 could regulate METTL3-or IGF2BP2-mediated m6A modification, further activating the RIG-I-like receptor signaling pathway in Vγ9Vδ2 T cells. Moreover, blocking the RIG-I-like receptor signaling pathway reversed the effects of exosomal THBS1 on the function of Vγ9Vδ2 T cells. In addition, THBS1 was expressed at low levels in GC tissues and was associated with an unfavorable prognosis in GC patients. In sum, our findings indicate that exosomal THBS1 derived from GC cells enhanced the function of Vγ9Vδ2 T cells by activating the RIG-I-like signaling pathway in a m6A methylation-dependent manner. Targeting the exosomal THBS1/m6A/RIG-I axis may have important implications for GC immunotherapy based on Vγ9Vδ2 T cells.

Keywords: Exosome; Gastric cancer; N6-methyladenosine; THBS1; Vγ9Vδ2 T cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Methylation
Methyltransferases / metabolism
Prognosis
RNA-Binding Proteins / metabolism
Receptors, Antigen, T-Cell, gamma-delta / metabolism
Signal Transduction
Stomach Neoplasms* / pathology

Substances

IGF2BP2 protein, human
Methyltransferases
METTL3 protein, human
Receptors, Antigen, T-Cell, gamma-delta
RNA-Binding Proteins
thrombospondin-1, human