Mast cells boost anti-tumor potency of MAIT cells via inflammasome-dependent secretion of IL-18, 2025, Fan et al.

SNT Gatchaman

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Mast cells boost anti-tumor potency of MAIT cells via inflammasome-dependent secretion of IL-18
Fan, Fanfan; Wang, Jun; Liu, Kun; Zhang, Shiyue; Gao, Jian; Li, Xiongfei; Ma, Jiaqiang; Zhao, Yue; Li, Teng; Su, Han; Yang, Xinfeng; Han, Han; Huang, Qingyuan; Zhang, Yiliang; Pan, Yunjian; Ye, Ting; Hu, Hong; Sun, Yihua; Li, Fei; Cao, Zhiwei; Zhang, Yang; Zhang, Xiaoming; Chen, Haiquan

Mast cells (MC) serve as pivotal sentinels in the regulation of immune responses and inflammation, yet their function in lung adenocarcinoma (LUAD) remains largely neglected. To decode their heterogeneity, we perform single-cell transcriptomic analysis of LUAD-infiltrating MCs. Our study uncovers the complexity in MC composition and identifies 9 distinct states, including proinflammation, chemotaxis, and antigen presentation. The proinflammatory MC subset, characterized by high IL-18 expression, is associated with improved outcomes for LUAD patients.

This pro-inflammatory property is regulated by the activation of NLRP3 inflammasome within MCs, resulting in the formation of GSDMD pores and successive pyroptosis. Moreover, these MCs enhance the innate-like anti-tumor activity of MAIT cells by upregulating NKG2D and IFN-γ through the cytokine-activation mechanism.

Our results uncover an unappreciated state of MCs and describe an inflammasome-dependent, MC-mediated regulation of MAIT cells in LUAD. These findings diversify our understanding of the functional repertoire and mechanistic equipment of MCs and MAIT cells, and suggest a potential therapeutic target for cancer treatment.

Link | PDF | Nature Communications [Open Access]
 
While interactions between MCs and T cells have been reported, direct evidence linking MCs and MAIT cells has been lacking. Our results uncover a novel mechanism of MAIT cell activation by MCs, driven by IL-18, a cytokine known to activate MAIT cells in other contexts such as COVID-19. We demonstrate that MC-derived IL-18 enhances MAIT cell activation via a cytokine-dependent pathway. Activated MAIT cells upregulated IFN- γ , which was reported to enhance the anti-tumor function of NK cells.
 
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