Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies.

Cell Stem Cell

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Precision Immunotherapy Alliance, Institute for Cancer Research, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Electronic address:

Published: September 2024

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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stem.2024.06.011DOI Listing

Publication Analysis

Top Keywords

adhesion ligands
16
rejection host
12
genetic ablation
8
ablation adhesion
8
allogeneic cellular
8
cellular immunotherapies
8
donor cells
8
host immune
8
rejection
6
cells
6

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!