Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor...

Area of Science:

• Immunology
• Oncology
• Gene Therapy

Background:

• Immunotherapy is a key cancer treatment, but many patients do not respond due to immunosuppressive tumor microenvironments (TME).
• Overcoming TME-mediated immunosuppression is crucial for effective cancer therapies.

Purpose of the Study:

• To investigate the efficacy of monocyte-mediated gene delivery of interferon-alpha (IFNα) in inhibiting leukemia.
• To determine if IFNα gene therapy can reprogram the immunosuppressive TME and enhance anti-leukemia immune responses.

Main Methods:

• Utilized a mouse model of leukemia.
• Administered monocyte-mediated gene delivery of IFNα.
• Performed bulk and single-cell transcriptome analyses to assess TME reprogramming.
• Evaluated T-cell priming, effector function, and anti-tumor activity.

Main Results:

• IFNα gene therapy inhibited leukemia growth by counteracting immunosuppressive myeloid cells and creating an immunostimulatory TME.
• Transcriptome analyses confirmed TME reprogramming, promoting T-cell priming and effector functions.
• Durable responses were observed, enhanced by combining gene therapy with checkpoint inhibitors.
• IFNα gene therapy improved the anti-tumor activity of adoptively transferred T cells (TCR/CAR engineered).

Conclusions:

• Monocyte-mediated IFNα gene therapy is a potent strategy for reprogramming the immunosuppressive TME in leukemia.
• This approach enhances endogenous and adoptively transferred T-cell anti-leukemia activity.
• The findings support further investigation for clinical development of this gene therapy strategy.