Therapeutic 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.  While not observed in mouse ILC2s, we have 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 FOXO1. Over time, the high surface density expression of CD155 in AML impairs 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 profile has been validated by single-cell RNA sequencing. In both AML and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a new member of the cytolytic immune effector cell family. Overall design: Identification of the phenotypes of expanded ILC2s and freshly isolated ILC2s from PBMCs