TGF-βR/IL-2R 免疫调节融合蛋白将免疫抑制转化为 T 细胞激活以增强过继性 T 细胞治疗

Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF- and insufficient survival/proliferative signals within the tumor microenvironment (TME).

We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF- signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF- R/IL-2R IFPs were constructed by fusing extracellular domains of the TGF- receptor chains with intracellular domains of IL-2R and IL-2R to enable TGF- 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- 1, and simultaneously reduced canonical SMAD2/3 signaling.

IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF- 1, effectively leveraging TGF- -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- .

Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF- 1, highlighting both neutralization of TGF- -mediated suppression and enhanced proliferation. TGF- R/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.