Taking advantage of low IL-9R expression in normal tissues, Jiang et al. engineered T cells with wild-type IL-9R. After transfer into tumor-bearing mice in combination with IL-9, which was well tolerated, IL-9R-engineered T cells showed enhanced infiltration, stemness, and antitumor activity compared to similar studies with orthogonal IL-9R. The IL-9–IL-9R axis activated STAT1/3/5 and (unexpectedly) recruited STAT4, and was highly sensitive to alterations in IL-9R signal strength or pSTAT stoichiometry. Levels of pSTAT1 determined differentiation towards stem/memory or terminal effector states. Similar results were observed CAR T cells.
Contributed by Lauren Hitchings
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.
Author Info: (1) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Molecular and Cellular Physiology and Structural Biology, Stan
Author Info: (1) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (2) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (3) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94143, USA; Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA 94143, USA. (4) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (5) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (6) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (7) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (8) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (9) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (10) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (11) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (12) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA. (13) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (14) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (15) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (16) Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, Los Angeles, CA 90095, USA. (17) Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Pediatric Hematology-Oncology, University of California, Los Angeles, Los Angeles, CA 90095, USA. (18) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94143, USA. (19) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, 1 Letterman Drive, Suite D3500, San Francisco, CA 94129, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. (20) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA 94143, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94143, USA. Electronic address: akalbasi@stanford.edu.
