Highlights
- •Human (h)ILC2s secrete GZMB and directly lyse tumor cells via pyroptosis/apoptosis
- •ILC2s fail to produce GZMB in acute myeloid leukemia (AML) patients, a mechanism of tumor immune evasion
- •hILC2s can be reliably expanded ex vivo, validated as authentic hILC2s by scRNA-seq
- •Infusion of expanded hILC2s protects against progression of liquid and solid tumors
Summary
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 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 member of the cytolytic immune effector cell family.
