Li, Ma, Tang, et al. developed a technique to study human group 2 innate lymphoid cell (ILC2) functions by expanding blood-obtained ILC2 ex vivo (ex ILC2s). Ex ILC2s were at an intermediate activation state and maintained the ILC2 phenotype. Ex ILC2 were able to kill AML cells in vitro and control tumor growth in AML mouse models. ILC2-mediated tumor killing was dependent on DNAM-1 interacting with its ligands, CD122 and CD155, which led to downstream inactivation of FOXO1 and production of granzyme B, triggering apoptosis or pyroptosis. High tumoral CD155 levels suppressed DNAM-1 on ILC2, resulting in immune evasion. ILC2s also had potential antitumor activity against solid tumors.
Contributed by Maartje Wouters
ABSTRACT: 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.