An engineered viral protein activates STAT5 to prevent T cell suppression.

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• T cell therapy efficacy is limited by Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling dysregulation.
• Maintaining STAT signaling is crucial for sustained T cell functionality and anti-tumor responses.

Purpose of the Study:

• To engineer a method for direct STAT protein activation in T cells.
• To enhance T cell survival and cytotoxic function independently of external cytokines.
• To improve T cell persistence and efficacy in solid tumor microenvironments.

Main Methods:

• Engineered herpesvirus saimiri tyrosine kinase interacting protein (TIP) to recruit LCK kinase to STAT proteins.
• Combined TIP-binding LCK region with STAT-binding sites from cytokine receptors.
• Utilized STAT5 activator to sustain CD8+ T cell function ex vivo and in vivo.
• Performed single-cell transcriptomics to analyze T cell fate and gene expression.

Main Results:

• Developed a cytokine-independent STAT activation system in T cells.
• Demonstrated STAT5 activator sustained CD8+ T cell survival and cytotoxic function ex vivo without interleukin-2.
• Observed reduced tumor outgrowth in vivo due to enhanced T cell persistence and functionality.
• Identified prevention of T cell exhaustion-associated gene expression by the STAT5 activator.

Conclusions:

• Rewiring T cell signaling pathways can sustain T cell function in solid tumors.
• Engineered STAT activation offers a potential strategy to overcome limitations in T cell-based cancer therapies.
• Targeted STAT activation can enhance the therapeutic potential of T cells by improving their persistence and function.