Bioengineered iPSC-derived human macrophages with increased angiotensin-converting enzyme (ACE) expression suppress...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• The immune system plays a crucial role in controlling cancer progression.
• Innovative immunotherapies are being developed to harness anti-cancer immunity.
• Macrophages are key immune cells with potential for therapeutic manipulation.

Purpose of the Study:

• To investigate engineered human macrophages expressing regulatable angiotensin-converting enzyme (ACE) as a novel anti-cancer immunotherapy.
• To evaluate the anti-tumor efficacy of ACE-expressing macrophages (ACE-iMac) in vitro and in vivo.

Main Methods:

• Genetically engineered induced pluripotent stem cell-derived macrophages (iMac) with doxycycline-inducible ACE expression.
• Assessment of macrophage polarization towards M1 phenotype and cytokine production.
• In vitro tumor cell killing assays.
• In vivo studies using xenograft models (melanoma, breast cancer, HNSCC) and a humanized BLT-NSG mouse model.

Main Results:

• ACE-iMac exhibited enhanced M1 polarization, increased proinflammatory cytokine production, and superior tumor cell killing in vitro compared to iMac.
• Significant reductions (3.4- to 7.2-fold) in solid tumor size were observed in vivo across multiple cancer types.
• ACE-iMac treatment enhanced human T cell and NK cell activation in a humanized mouse model, reducing melanoma xenograft growth.

Conclusions:

• Enhancing ACE expression in human macrophages amplifies their anti-cancer phenotype.
• ACE-iMac represents a promising novel immunotherapy strategy for various cancers.
• This approach has the potential to improve clinical outcomes for cancer patients.