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Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin.

Benjamin Ruf1, Matthias Bruhns2, Sepideh Babaei3

  • 1Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Cell
|August 18, 2023
PubMed
Summary

Mucosal-associated invariant T (MAIT) cells are dysfunctional in liver cancer, failing to infiltrate tumors. Targeting tumor-associated macrophages that interact with MAIT cells may restore their anti-cancer activity.

Keywords:
CODEXHCCMAIT cellsS(3)-CIMAaPD-1/aPD-L1immunotherapyinnate-like T cellsmucosal-associated invariant T cellstumor immune microenvironmenttumor-associated macrophages

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Area of Science:

  • Immunology
  • Oncology
  • Hepatology

Background:

  • Mucosal-associated invariant T (MAIT) cells are abundant innate-like T cells in the human liver.
  • MAIT cells play roles in immunity and inflammation, but their function in liver cancer is unclear.

Purpose of the Study:

  • To investigate the role and characteristics of MAIT cells in hepatocellular carcinoma (HCC).
  • To explore the cellular interactions affecting MAIT cell function in the HCC microenvironment.

Main Methods:

  • Single-cell RNA sequencing (scRNA-seq) and flow cytometry on paired HCC patient samples.
  • Co-detection by indexing (CODEX) imaging for spatial analysis of the tumor microenvironment.
  • Machine-learning tools to analyze cellular interaction networks.
  • Ex vivo co-culture studies and murine models to perturb cell-cell interactions.

Main Results:

  • MAIT cells in HCC exhibit heterogeneity and dysfunctionality, with impaired infiltration into liver tumors.
  • A specific interaction between MAIT cells and CSF1R+PD-L1+ tumor-associated macrophages (TAMs) was identified as a key factor in MAIT cell dysfunction.
  • Perturbing this TAM-MAIT cell interaction restored MAIT cell cytotoxicity in experimental models.

Conclusions:

  • MAIT cell dysfunction is a feature of HCC, influenced by interactions with specific TAMs.
  • Targeting the interaction between TAMs and MAIT cells can enhance MAIT cell anti-tumor activity.
  • These findings suggest that therapies targeting PD-1/PD-L1 may impact MAIT cells in HCC patients.