A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy

• 成果类型: Article
• 署名作者: Su, Yapeng; Thelen, Ashley; Wirth, Lena V.; Jenkins, Cody M.; Mak, Sam R.; Chen, Daniel G.; Gottardo, Raphael; Greenberg, Philip D.
• 署名单位: Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center; Wellcome Trust Sanger Institute; University of Cambridge; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14243
• DOI: 10.1073/pnas.2516951122
• 发表日期: 2025-09-30
• 关键词: tgf-beta; cytoplasmic domains; metastatic melanoma; il-2 receptor; interleukin-2; antigen; signal; growth-factor-beta-1; proliferation; RECOGNITION

摘要

Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-f3 and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-f3 signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-f3R/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-f3 receptor chains with intracellular domains of IL-2Rf3 and IL-2R gamma to enable TGF-f3 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-f31, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-f31, effectively leveraging TGF-f3-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-f3. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-f31, highlighting both neutralization of TGF-f3-mediated suppression and enhanced proliferation. TGF-f3R/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.