Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression

Nat Biomed Eng. 2024 Apr;8(4):443-460. doi: 10.1038/s41551-024-01195-6. Epub 2024 Apr 1.

Abstract

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism
  • Cytokines / metabolism
  • Graft vs Host Disease* / immunology
  • Humans
  • Immunosuppression Therapy* / methods
  • Mesenchymal Stem Cell Transplantation / methods
  • Mesenchymal Stem Cells* / cytology
  • Mesenchymal Stem Cells* / immunology
  • Mesenchymal Stem Cells* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / immunology
  • Receptors, Chimeric Antigen* / metabolism
  • T-Lymphocytes / immunology

Substances

  • Receptors, Chimeric Antigen
  • Cadherins
  • Cytokines