biostudies-literatureLi ZNIAID NIH HHSNational Cancer InstituteNCI NIH HHSNINDS NIH HHSNational Institutes of HealthCalifornia Institute for Regenerative MedicineNIAMS NIH HHSLeukemia and Lymphoma Society624-641.e23https://www.ebi.ac.uk/biostudies/studies/S-EPMC11442011biostudies-literatureUnknown187(3)The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2sCellTherapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.PMC11442011TRAN1-14716R01 CA266457CA264512P01 CA163205CA266457R21 CA223400AI129582R01 CA247550R01 AR070116CA265095CA210087NS106170R01 NS106170P30 CA033572DISC2-14190R01 CA265095P30CA033572R35 CA210087CA223400CA163205CA247550U19 CA264512TRAN1-140031364–19R01 AI129582Artis DMa RLi ZGuo JZhang JLiu NCao SMarcucci GYu JCaligiuri MATang HShah ZfalseTherapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s2024-01-01T00:00:00Z2024 Feb2026-06-01T18:12:06.874Z2025-04-05T19:19:18.416ZS-EPMC114420113821159010.1016/j.cell.2023.12.015