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

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.