Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies

Cell Stem Cell. 2024 Sep 5;31(9):1376-1386.e8. doi: 10.1016/j.stem.2024.06.011. Epub 2024 Jul 8.

Abstract

Allogeneic cellular immunotherapies hold promise for broad clinical implementation but face limitations due to potential rejection of donor cells by the host immune system. Silencing of beta-2 microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection by the host, although the absence of B2M is expected to trigger missing-self responses by host natural killer (NK) cells. Here, we demonstrate that genetic deletion of the adhesion ligands CD54 and CD58 in B2M-deficient chimeric antigen receptor (CAR) T cells and multi-edited induced pluripotent stem cell (iPSC)-derived CAR NK cells reduces their susceptibility to rejection by host NK cells in vitro and in vivo. The absence of adhesion ligands limits rejection in a unidirectional manner in B2M-deficient and B2M-sufficient settings without affecting the antitumor functionality of the engineered donor cells. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection by host immune cells, facilitating the implementation of universal immunotherapy.

Keywords: CAR T cells; CD54; CD58; allogeneic cell therapy; hyopimmune; iPSC-derived NK cells; immune evasion; immune synapse; natural killer cells.

MeSH terms

  • Animals
  • CD58 Antigens / genetics
  • CD58 Antigens / metabolism
  • Graft Rejection / immunology
  • Humans
  • Immunotherapy / methods
  • Induced Pluripotent Stem Cells / metabolism
  • Intercellular Adhesion Molecule-1 / metabolism
  • Killer Cells, Natural* / immunology
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Chimeric Antigen / immunology
  • Receptors, Chimeric Antigen / metabolism
  • beta 2-Microglobulin / genetics
  • beta 2-Microglobulin / metabolism

Substances

  • Ligands
  • CD58 Antigens
  • beta 2-Microglobulin
  • Receptors, Chimeric Antigen
  • Intercellular Adhesion Molecule-1