Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway

Area of Science:

• Immunology
• Metabolomics
• Cancer Biology

Background:

• Mucosal-associated invariant T (MAIT) cells are crucial immune cells recognizing microbial metabolites.
• The specific ligands recognized by MAIT cells in the context of cancer are largely unknown.
• Folate metabolism is frequently altered in cancer cells.

Purpose of the Study:

• To identify tumor-derived metabolites that activate MAIT cells.
• To investigate the role of folate metabolism in MAIT cell activation within a cancer setting.
• To characterize the interaction between tumor metabolites and MAIT cell receptors.

Main Methods:

• Treatment of mouse MAIT cells with tumor-derived metabolites, including 5-formyl tetrahydrofolate (5-formyl THF).
• Enzymatic assays using Amino methyltransferase (Amt) to assess 5-formyl THF generation.
• Genetic manipulation of tumors (Amt deletion and overexpression) to study MAIT cell activation.
• TCR transfer experiments into MAIT cell-deficient T cells.
• Single-cell TCR sequencing in human samples.

Main Results:

• 5-formyl THF, a folate metabolism intermediate, was identified as a tumor-derived metabolite that induces T cell receptor (TCR)-dependent activation of mouse MAIT cells.
• The enzyme Amino methyltransferase (Amt) is essential for generating 5-formyl THF in tumor cells, directly impacting MAIT cell activation.
• Genetic deletion of Amt impaired MAIT cell activation, while Amt overexpression enhanced it.
• A 5-formyl THF-reactive MAIT cell clonotype was identified in humans via single-cell TCR sequencing.

Conclusions:

• 5-formyl THF is the first identified tumor-derived ligand that activates MAIT cells in both mice and humans.
• The folate metabolism pathway, specifically through Amt, plays a critical role in generating MAIT cell-activating ligands in cancer.
• Further research is needed to determine the in vivo functional significance of this tumor-MAIT cell interaction pathway.