摘要：SummaryAllo-HSCT is a curative therapy for hematologic malignancies owing to GvL effect mediated by alloreactive T cells; however, the same T cells also mediate GvHD, a severe side effect limiting the widespread application of allo-HSCT in clinics. Invariant natural killer T (iNKT) cells can ameliorate GvHD while preserving GvL effect, but the clinical application of these cells is restricted by their scarcity. Here, we report the successful generation of third-party HSC-engineered human iNKT (3rdHSC-iNKT) cells using a method combining HSC gene engineering andin vitroHSC differentiation. The3rdHSC-iNKT cells closely resembled the CD4−CD8−/+subsets of endogenous human iNKT cells in phenotype and functionality. These cells displayed potent anti-GvHD functions by eliminating antigen-presenting myeloid cellsin vitroand in xenograft models without negatively impacting tumor eradication by allogeneic T cells in preclinical models of lymphoma and leukemia, supporting3rdHSC-iNKT cells as a promising off-the-shelf cell therapy candidate for GvHD prophylaxis.Graphical abstractDisplay OmittedHighlights•3rdHSC-iNKT cells are generated off-the-shelf at high yield and purity•3rdHSC-iNKT cells ameliorate GvHD while preserving GvL effect•3rdHSC-iNKT cells effectively target antigen-presenting myeloid cells through CD1d•3rdHSC-iNKT cell product is a therapy candidate for GvHD prophylaxis in allo-HSCTBiomedical engineering; Cell engineering; Immunology; Stem cells research
