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

Cell. 2023 Aug 17;186(17):3686-3705.e32. doi: 10.1016/j.cell.2023.07.026.

Abstract

Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we present a MAIT cell-centered profiling 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. Machine-learning tools were used to dissect the spatial cellular interaction network within the MAIT cell neighborhood. 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 in ex vivo co-culture studies using patient samples and murine models reinvigorated MAIT cell cytotoxicity. These studies suggest that aPD-1/aPD-L1 therapies target MAIT cells in HCC patients.

Keywords: CODEX; HCC; MAIT cells; S(3)-CIMA; aPD-1/aPD-L1; immunotherapy; innate-like T cells; mucosal-associated invariant T cells; tumor immune microenvironment; tumor-associated macrophages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular* / immunology
  • Carcinoma, Hepatocellular* / pathology
  • Humans
  • Liver Neoplasms* / immunology
  • Liver Neoplasms* / pathology
  • Mice
  • Mucosal-Associated Invariant T Cells* / immunology
  • Mucosal-Associated Invariant T Cells* / pathology
  • Tumor-Associated Macrophages