Activating Mucosal-Associated Invariant T (MAIT) cells for next generation immunotherapy of liver cancer

Introduction: Mucosal-associated invariant T (MAIT) cells represent up to 30-40% of T cells in the liver and they play a crucial role in the regulation of immunity and inflammation. We have recently shown that MAIT cells can contribute to anti-tumor activity in mice when activated and expanded with a prototypic activating MAIT T cell receptor ligand, 5-OP-RU. The aim of this work was to resolve the underlying mechanisms of MAIT-mediated anti-tumor immunity. Methods: Syngeneic mouse models of orthotopic primary liver cancer and liver metastases were used to study anti-tumor activity of MAIT cells. A series of pharmacological depletion experiments and genomic conditional knockout mouse strains were used to identify additional effector immune cells and humoral factors that mediate this effect. Single-cell RNA sequencing and high-dimensional flow cytometry provided crucial clues to underlying mechanisms. Results: Combination immunotherapy of 5-OP-RU and CpG induced a strong systemic in vivo expansion and activation of MAIT. We show that MAIT cells are potent mediators of this anti-tumor activity across various models of liver cancer in vivo when activated by 5-OP-RU/CpG. Additional pharmacological depletion experiments and genomic conditional knockout mouse strains helped to identify effector cells and co-stimulatory effector molecules as critical components required for MAIT-induced tumor suppression. Conclusion: MAIT cells play an important role in tumor immunology and represent an attractive new target for immunotherapy. Finely tuned, context-dependent mechanisms determine MAIT cell function in vivo. Targeted by treatment with MAIT ligand 5-OP-RU, they recruit a network of anti-tumor effector cells for liver cancer control. Publication History Article published online: 20 January 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany