Invited Speaker CD1-MR1 Workshop 2025

MAIT cell activation inhibits tumor growth in the liver (#60)

Tim Greten 1
  1. National Cancer institute, Bethesda, MARYLAND, United States

Current Immunotherapeutic strategies have primarily focused on checkpoint inhibitors targeting conventional T cells.  Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver 1. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. We have previously profiled MAITs in the context of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAIT cells in HCC and their defective capacity to infiltrate liver tumors. Co-localization in the adjacent liver and interaction between niche-occupying CSF1R+PD-L1+ tumor-associated macrophages (TAMs) and MAIT cells was identified as a key regulatory element of MAIT cell dysfunction. Perturbation of this cell-cell interaction reinvigorated MAIT cell cytotoxicity 2. Activation of MAITs using 5-OP-RU and CpG led to anti-tumor immunity in murine liver cancer models 3. We are currently studying how MAIT cell exert their anti-tumor function in the liver.

  1. Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol. 2021;18(1):112-27. Epub 20201124. doi: 10.1038/s41423-020-00572-w. PubMed PMID: 33235387; PMCID: PMC7852696.
  2. Ruf B, Bruhns M, Babaei S, Kedei N, Ma L, Revsine M, Benmebarek MR, Ma C, Heinrich B, Subramanyam V, Qi J, Wabitsch S, Green BL, Bauer KC, Myojin Y, Greten LT, McCallen JD, Huang P, Trehan R, Wang X, Nur A, Murphy Soika DQ, Pouzolles M, Evans CN, Chari R, Kleiner DE, Telford W, Dadkhah K, Ruchinskas A, Stovroff MK, Kang J, Oza K, Ruchirawat M, Kroemer A, Wang XW, Claassen M, Korangy F, Greten TF. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin. Cell. 2023;186(17):3686-705 e32. doi: 10.1016/j.cell.2023.07.026. PubMed PMID: 37595566; PMCID: PMC10461130.
  3. Ruf B, Catania VV, Wabitsch S, Ma C, Diggs LP, Zhang Q, Heinrich B, Subramanyam V, Cui LL, Pouzolles M, Evans CN, Chari R, Sakai S, Oh S, Barry CE, 3rd, Barber DL, Greten TF. Activating Mucosal-Associated Invariant T Cells Induces a Broad Antitumor Response. Cancer Immunol Res. 2021;9(9):1024-34. Epub 20210630. doi: 10.1158/2326-6066.CIR-20-0925. PubMed PMID: 34193462; PMCID: PMC8416791.