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

BACKGROUND AIMS The innate-like mucosa-associated invariant T (MAIT) cells are enriched in human liver and have been linked to human hepatocellular carcinoma (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 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. Additionally, 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 anti-tumor 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 neuro-immune crosstalk.

[1]  C. Leslie,et al.  Single-Cell Transcriptional Profiling Reveals Signatures of Helper, Effector, and Regulatory MAIT Cells during Homeostasis and Activation , 2022, The Journal of Immunology.

[2]  P. Klenerman,et al.  Stimulatory MAIT cell antigens reach the circulation and are efficiently metabolised and presented by human liver cells , 2022, Gut.

[3]  Jun‐liang Fu,et al.  Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B. , 2021, Journal of hepatology.

[4]  J. Zucman‐Rossi,et al.  Hepatocellular carcinoma , 1998, Nature Reviews Disease Primers.

[5]  C. Aspord,et al.  Circulating IL-13 Is Associated with De Novo Development of HCC in HCV-Infected Patients Responding to Direct-Acting Antivirals , 2020, Cancers.

[6]  N. Nagarajan,et al.  Human Tumor-Infiltrating MAIT Cells Display Hallmarks of Bacterial Antigen Recognition in Colorectal Cancer , 2020, Cell reports. Medicine.

[7]  J. McCluskey,et al.  IL-17 production by tissue-resident MAIT cells is locally induced in children with pneumonia , 2020, Mucosal Immunology.

[8]  S. Sakaguchi,et al.  Regulatory T Cells and Human Disease. , 2020, Annual review of immunology.

[9]  P. Klenerman,et al.  MAIT Cells in Health and Disease. , 2020, Annual review of immunology.

[10]  D. Fairlie,et al.  MAIT cells promote tumor initiation, growth and metastases via tumor MR1. , 2019, Cancer discovery.

[11]  Matthew E. Ritchie,et al.  A divergent transcriptional landscape underpins the development and functional branching of MAIT cells , 2019, Science Immunology.

[12]  B. Hylander,et al.  β2 Adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. , 2019, The Journal of clinical investigation.

[13]  S. Lotersztajn,et al.  Mucosal-associated invariant T cells and disease , 2019, Nature Reviews Immunology.

[14]  A. Trautmann,et al.  Blockade of β-Adrenergic Receptors Improves CD8+ T-cell Priming and Cancer Vaccine Efficacy , 2019, Cancer Immunology Research.

[15]  J. McCluskey,et al.  The biology and functional importance of MAIT cells , 2019, Nature Immunology.

[16]  D. Pellicci,et al.  Chronically stimulated human MAIT cells are unexpectedly potent IL‐13 producers , 2019, Immunology and cell biology.

[17]  Q. Gao,et al.  Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate Poor Outcome in Hepatocellular Carcinoma , 2019, Clinical Cancer Research.

[18]  F. Legoux,et al.  A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets , 2018, The Journal of experimental medicine.

[19]  D. Nixon,et al.  The CD4−CD8− MAIT cell subpopulation is a functionally distinct subset developmentally related to the main CD8+ MAIT cell pool , 2018, Proceedings of the National Academy of Sciences.

[20]  D. Thorburn,et al.  MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation , 2018, Hepatology.

[21]  R. Gottardo,et al.  Human MAIT cells exit peripheral tissues and recirculate via lymph in steady state conditions. , 2018, JCI insight.

[22]  E. Sloan,et al.  β-Adrenergic Signaling Impairs Antitumor CD8+ T-cell Responses to B-cell Lymphoma Immunotherapy , 2017, Cancer Immunology Research.

[23]  Boxi Kang,et al.  Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing , 2017, Cell.

[24]  F. Sánchez‐Madrid,et al.  CD69: from activation marker to metabolic gatekeeper , 2017, European journal of immunology.

[25]  T. Curiel,et al.  Suppressive IL-17A+Foxp3+ and ex-Th17 IL-17AnegFoxp3+ Treg cells are a source of tumour-associated Treg cells , 2017, Nature Communications.

[26]  A. Lehuen,et al.  Lights on MAIT cells, a new immune player in liver diseases. , 2016, Journal of Hepatology.

[27]  P. Klenerman,et al.  Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1 , 2016, Journal of hepatology.

[28]  A. Sönnerborg,et al.  Arming of MAIT Cell Cytolytic Antimicrobial Activity Is Induced by IL-7 and Defective in HIV-1 Infection , 2015, PLoS pathogens.

[29]  R. Flavell,et al.  Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells , 2015, Nature Immunology.

[30]  P. Klenerman,et al.  CD161++CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner , 2013, European journal of immunology.

[31]  A. Keller,et al.  Beta2‐adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA‐dependent manner , 2013, European journal of immunology.

[32]  Malcolm J. McConville,et al.  MR1 presents microbial vitamin B metabolites to MAIT cells , 2012, Nature.

[33]  R. Xiao,et al.  β-adrenergic receptor subtype signaling in the heart: from bench to the bedside. , 2011, Current topics in membranes.

[34]  H. Jones,et al.  Epinephrine-primed murine bone marrow-derived dendritic cells facilitate production of IL-17A and IL-4 but not IFN-γ by CD4+ T cells , 2010, Brain, Behavior, and Immunity.

[35]  D. Littman,et al.  Identification of IL-17-producing FOXP3+ regulatory T cells in humans , 2009, Proceedings of the National Academy of Sciences.

[36]  T. Ley,et al.  Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. , 2007, Immunity.

[37]  A. Takaki,et al.  The hepatic sympathetic nerve plays a critical role in preventing Fas induced liver injury in mice , 2005, Gut.

[38]  N. Sinelli,et al.  Hepatic fibrogenesis requires sympathetic neurotransmitters , 2004, Gut.

[39]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[40]  P. Calabresi,et al.  Activation of β1-Adrenoceptors Excites Striatal Cholinergic Interneurons through a cAMP-Dependent, Protein Kinase-Independent Pathway , 2003, The Journal of Neuroscience.