IL7-TBRII, a Dual Cytokine Modulator Targeting IL-7 and TGF-β Pathways, Inhibits Tumor Progression and Metastasis.

Area of Science:

• Immunology
• Cancer Biology
• Biotechnology

Background:

• Tumor-infiltrating CD8+ T cells are crucial for immunotherapy efficacy.
• Interleukin-7 (IL-7) therapy shows promise for expanding CD8+ T cells but faces limitations due to the immunosuppressive tumor microenvironment.
• Elevated TGF-β signaling in CD8+ T cells following IL-7 treatment impairs their function and antagonizes IL-7 signaling.

Purpose of the Study:

• To develop a novel bifunctional fusion protein to overcome IL-7 therapy limitations.
• To enhance anti-tumor efficacy by simultaneously modulating IL-7 and TGF-β pathways.
• To evaluate the therapeutic potential of the IL7-TBRII fusion protein in preclinical cancer models.

Main Methods:

• Developed a bifunctional fusion protein (IL7-TBRII) by linking recombinant human IL-7 (rhIL-7)-hyFc to a TGF-β trap (Fc-TBRII).
• Evaluated binding affinities and functionalities of IL7-TBRII domains in vitro and in vivo.
• Assessed anti-tumor effects in MC38 colon cancer, 4T1 breast cancer, and EMT6 breast tumor models, including combination therapies.

Main Results:

• IL7-TBRII demonstrated superior anti-tumor efficacy compared to individual components, primarily by increasing cytotoxic CD8+ T cell infiltration.
• IL7-TBRII expanded the population of activated CD44+ CD8+ T cells.
• Reduced metastasis in the 4T1 model and showed synergistic effects with radiotherapy or anti-CTLA-4 therapy in the EMT6 model.

Conclusions:

• Dual modulation of IL-7 and TGF-β pathways by IL7-TBRII effectively reprograms the tumor immune microenvironment.
• IL7-TBRII promotes CD8+ T cell activation and infiltration, offering a promising strategy to improve immunotherapy clinical responses.
• This bifunctional approach holds potential for treating both primary and metastatic tumors.