Su and Thelen et al. showed that engineering human CD8+ T cells with fusions of the TGFβRI and -II extracellular ligand-binding domains and IL-2Rβ and -γ intracellular domains rewired TGF-β1 signalling to activate the IL-2 pathway and enhance effector functions while allowing maintenance of self-renewal potential and reducing SMAD2/3 TGFβR inhibitory signaling. In TGFβ-rich conditions, transgene+ CD8+ T cells outcompeted untransduced human CD8+ T cells. Coexpressing TGFβR/IL-2Rβγ with a mesothelin-specific TCR in human CD8+ T cells boosted tumor cell killing and T cell expansion in the presence of TGFβ1 in vitro.
Contributed by Paula Hochman
ABSTRACT: Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-β and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-β signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-βR/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-β receptor chains with intracellular domains of IL-2Rβ and IL-2Rγ to enable TGF-β binding to trigger STAT5 phosphorylation and activate the downstream IL-2 pathway. In human primary CD8+ T cells, select IFP designs robustly induced p-STAT5 upon exposure to TGF-β1, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-β1, effectively leveraging TGF-β-rich conditions to outcompete nontransduced cells. Transcriptomic analyses revealed that IFP signaling promoted T cell activation and allowed maintenance of stemness during culture with TGF-β. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-β1, highlighting both neutralization of TGF-β-mediated suppression and enhanced proliferation. TGF-βR/IL-2R IFPs appear promising for reprogramming the signals T cells receive in the TME and improving efficacy of adoptive T cell therapy in solid tumors.
Author Info: (1) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. Herbold Computational Biology Program, Vaccine and Inf
Author Info: (1) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. Herbold Computational Biology Program, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. (2) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. (3) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. (4) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. (5) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. (6) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. Department of Cellular Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton CB10 1SA, United Kingdom. Cambridge Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AW, United Kingdom. (7) Division of Clinical Research and Innovation, Biomedical Data Science Centre, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland. (8) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109. Department of Immunology, University of Washington, Seattle, WA 98109. Department of Medicine/Oncology, University of Washington, Seattle, WA 98109.
