IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy.

ABSTRACT: Arming T cells with a synthetically orthogonal IL-9 receptor (o9R) permits facile engraftment and potent anti-tumor functions. We considered whether the paucity of natural IL-9R expression could be exploited for T cell immunotherapy given that, in mice, high doses of IL-9 were well-tolerated without discernible immune modulation. Compared to o9R, T cells engineered with IL-9R exhibit superior tissue infiltration, stemness, and anti-tumor activity. These qualities are consistent with a stronger JAK/STAT signal, which in addition to STAT1/3/5, unexpectedly includes STAT4 (canonically associated with IL-12 but not common γ-chain cytokines). IL-9R T cells are exquisitely sensitive to perturbations of proximal signaling, including structure-guided attenuation, amplification, and rebalancing of

SUBMITTER: Jiang H 

PROVIDER: S-EPMC11760723 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature