Persistent STAT5 activation reprograms the epigenetic landscape in CD4⁺ T cells to drive polyfunctionality and...

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Polyfunctional CD4+ T cells are crucial for effective antitumor immunity.
• The precise mechanisms driving the development of these cells remain an area of active research.
• Signal transducer and activator of transcription 5 (STAT5) is a key signaling molecule in T cell function.

Purpose of the Study:

• To investigate the role of STAT5 activation in the development of polyfunctional CD4+ T cells.
• To explore the therapeutic potential of STAT5 engineering in adoptive T cell therapy for cancer.

Main Methods:

• Ectopic expression of constitutively active murine STAT5A (CASTAT5) in tumor-specific CD4+ T cells.
• Adoptive transfer models in mice to assess T cell expansion, tumor infiltration, and antitumor responses.
• Integrated epigenomic and transcriptomic analysis, including single-cell RNA sequencing.
• Engineering chimeric antigen receptor (CAR) T cells with CASTAT5 for therapeutic evaluation.

Main Results:

• CASTAT5 expression led to robust expansion and enhanced tumor infiltration of CD4+ T cells.
• CASTAT5 induced significant chromatin remodeling and altered the transcriptional landscape of CD4+ T cells.
• A subset of CASTAT5-transduced CD4+ T cells exhibited a progenitor polyfunctional T cell signature.
• Adoptive transfer of CASTAT5-engineered CAR T cells improved therapeutic outcomes in a lymphoma model.
• Co-transduction of both CD4+ and CD8+ CAR T cells with CASTAT5 optimized therapeutic efficacy, highlighting enhanced CD4 help.

Conclusions:

• Persistent STAT5 activation is a key driver for generating polyfunctional, tumor-tropic CD4+ T cells.
• STAT5 engineering represents a promising strategy to enhance the efficacy of adoptive T cell therapy.
• CASTAT5 demonstrates functional activity in human CD4+ T cells, suggesting broad clinical applicability.