Mucosal-associated invariant T (MAIT) cells are MR1-resricted innate-like T cells that recognize non-peptide antigens including riboflavin derivates. They can be detected in both primary tumors and metastasis, yet their role in cancer is still unclear. In vitro activated MAIT cells have demonstrated anti-tumor activity suggesting their potential for cancer immunotherapy, but in vivo data is lacking.
We systemically administered a combination of the VitaminB2 synthesis pathway-derived antigen 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) with Toll-like receptor 9 agonist CpG for in vivo activation and expansion of MAIT cells. We used three different murine models of liver tumors, a lung metastases model and subcutaneous tumors across two different mouse strains, to assess anti-tumor activity of 5-OP-RU + CpG. Tumor growth over time was measured by in vivo bioluminescence imaging. Phenotypic changes of hepatic, pulmonary and tumor-infiltrating MAIT cells were detected by FLOW cytometry using MR1-tetramers. Immune cell monitoring was performed to identify alterations in the tumor microenvironment. A series of pharmacological depletion experiments was conducted to identify additional effector cells.
Here, to the best of our knowledge, we report first evidence of MAIT cell-mediated anti-tumor function in vivo when activated by a combination of 5-OP-RU and TLR 9 agonist CpG. Co-administration of 5-OP-RU and CpG induced a strong systemic in vivo expansion and activation of MAIT cells with high expression of activation makers like CD69, pronounced effector memory phenotype and upregulated effector molecules including interferon (IFN)-γ, granzyme B and perforin. MAIT-directed 5-OP-RU + CpG showed pronounced and consistent anti-tumor activity in all tumor models and prolonged mouse survival. Importantly, such tumor inhibition was absent in MAIT-deficient MR1-/- mice. Additional depletion studies showed that NK cells partially mediate the MAIT-induced tumor suppression.
Increasing evidence suggests that MAIT cells are important players in cancer immunology. MAITs undergo a phenotypic switch and massively expand in vivo upon 5-OP-RU + CpG treatment. These licensed and educated innate-like T cells can then mediate potent anti-tumor responses in murine models and represent an attractive novel target for cancer immunotherapy. We provide a framework for how TCR-dependent pathogenic role of MAITs in malignancies can be overcome using stimulatory agents.
Citation Format: Benjamin Ruf, Simon Wabitsch, Chi Ma, Laurence P. Diggs, Bernd Heinrich, Vanessa V. Catania, Varun Subramanyam, Linda Cui, Shunsuke Sakai, Sangmi Oh, Clifton E. Barry, Daniel L. Barber, Tim F. Greten. Activating mucosal-associated invariant T cells (MAITs) induces a broad anti-tumor response and offers a novel target for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 68.