Regulatory mucosa-associated invariant T cells controlled by β1 adrenergic receptor signaling contribute to hepatocellular carcinoma progression

Abstract

Background and Aims: The innate-like mucosa-associated invariant T (MAIT) cells are enriched in human liver and have been linked to human HCC. However, their contributions to the progression of HCC are controversial due to the heterogeneity of MAIT cells, and new MAIT cell subsets remain to be explored. Approach and Results: Combining single cell RNA sequencing (scRNA-seq) and flow cytometry analysis, we performed phenotypic and functional studies and found that FOXP3+ CXCR3+ MAIT cells in HCC patients were regulatory MAIT cells (MAITregs) with high immunosuppressive potential. These MAITregs were induced under Treg-inducing condition and predominantly from FOXP3− CXCR3+ MAIT cells, which displayed mild Treg-related features and represented a pre-MAITreg reservoir. In addition, the induction and function of MAITregs were promoted by β1 adrenergic receptor signaling in pre-MAITregs and MAITregs, respectively. In HCC patients, high proportion of the intratumoral MAITregs inhibited antitumor immune responses and was associated with poor clinical outcomes. Conclusions: Together, we reveal an immunosuppressive subset of MAIT cells in HCC patients that contributes to HCC progression, and propose a control through neuroimmune crosstalk.

Immune regulation and therapeutic application of T regulatory cells in liver diseases

“…Their development is triggered under Treg-promoting conditions like β1 adrenergic receptor signaling. Intriguingly, intra-tumoral MAITregs exert immune suppressive effects and are linked to unfavorable clinical outcomes in HCC patients ( 122 ).…”