Engineering IL-21 secretion in T cells using druggable ligand-responsive stabilized domains

Area of Science:

• Immunology
• Biotechnology
• Cell Therapy

Background:

• Cytokine immunotherapies often cause systemic toxicity and uncontrolled release.
• Precise control over cytokine delivery is crucial for effective and safe therapeutic applications.

Purpose of the Study:

• To develop a novel, druggable, ligand-dependent system for controlled Interleukin-21 (IL-21) secretion.
• To enhance the safety and efficacy of engineered T cell therapies through tunable cytokine control.

Main Methods:

• Utilized destabilization domains (DDs) to create a ligand-responsive IL-21 secretion system.
• Evaluated ER50 and Dihydrofolate Reductase (DHFR) domains for IL-21 regulation.
• Performed structural analysis of IL-21 fusion proteins to understand receptor interactions.
• Assessed IL-21 secretion effects on primary T cells and T stem-like (Tscm) cell differentiation.

Main Results:

• ER50 demonstrated sustained, ligand-responsive IL-21 secretion, offering superior control.
• N-terminal fusion enhanced IL-21 receptor binding, while C-terminal fusion weakened it.
• Controlled IL-21 secretion promoted Tscm cell differentiation and improved T cell persistence in vitro.
• The developed system provided reversible and tunable control over cytokine release.

Conclusions:

• The developed druggable, ligand-dependent IL-21 system offers a safer and more flexible approach for cytokine-based immunotherapies.
• This technology has significant potential for improving adoptive T cell therapy by enhancing T cell function and persistence.
• Precise control over cytokine secretion is key to overcoming toxicity and improving therapeutic outcomes in immunotherapy.