IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy
Hua Jiang, Sam P. Limsuwannarot, Kayla Kulhanek, Aastha Pal, Ossama Labiad, Lea Wenting Rysavy, Ada Wong, Leon Su, Sarah M. Cavender, Johnathon Soro, Stefano Testa, Heather Ogana, Deepa Waghray, Pingdong Tao, Kevin M. Jude, Christopher S. Seet, Gay M. Crooks, Everett J. Moding, K. Christopher García, Anusha Kalbasi
Abstract
Cytokines and their receptors enable precise tuning of T cell function. Leveraging this biology holds tremendous promise for optimizing antitumor immunity. Arming T cells with a synthetically orthogonal interleukin (IL)-9 receptor (o9R), for instance, permits facile engraftment and potent anti-tumor functions. Exploiting the paucity of wild-type IL-9R expression and the safety of high doses of IL-9, here, we showed that, compared with o9R, T cells engineered with wild-type IL-9R exhibited superior tissue infiltration, stemness, and anti-tumor activity. These qualities were consistent with a stronger Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal, which included canonically IL-12-driven STAT4 in addition to STAT1/3/5. IL-9R T cells were exquisitely sensitive to perturbations of proximal signaling, including structure-guided attenuation, amplification, and rebalancing of JAK/STAT signals. Biased IL-9R mutants showed that STAT1 acts as a rheostat between stem-like and effector states. In summary, we identify IL-9/IL-9R as a naturally orthogonal cytokine-receptor pair with an optimal JAK/STAT signaling profile for engineered T cell therapy.