Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis

Area of Science:

• Oncology
• Immunology
• Cancer Metastasis

Background:

• Metastasis is the primary cause of cancer mortality, necessitating a deeper understanding of the pre-metastatic niche.
• Key regulatory signals driving metastatic progression within this niche remain poorly understood.
• Myeloid cells are identified as key regulators of immune suppression during pre-metastatic niche formation.

Purpose of the Study:

• To identify and target immune suppression mechanisms within the pre-metastatic niche.
• To investigate the therapeutic potential of genetically engineered myeloid cells (GEMys) delivering Interleukin-12 (IL-12) to modulate the metastatic microenvironment.

Main Methods:

• Identification of a core immune suppression gene signature in the pre-metastatic niche, predominantly expressed by myeloid cells.
• Development and utilization of genetically engineered myeloid cells (GEMys) to deliver IL-12.
• Assessment of IL12-GEMy treatment effects on immune cell activity, tumor burden, and survival in preclinical cancer models.

Main Results:

• IL12-GEMy treatment effectively reversed immune suppression in the pre-metastatic niche.
• Treatment led to enhanced antigen presentation and T cell activation.
• Significant reduction in both metastatic and primary tumor burden was observed, alongside improved survival rates in tumor-bearing mice.

Conclusions:

• Genetically engineered myeloid cells delivering IL-12 can functionally modulate the immune suppressive program in the pre-metastatic niche.
• This strategy successfully rebalances the dysregulated metastatic microenvironment, offering a promising therapeutic avenue for cancer.
• Targeting myeloid-driven immune suppression represents a viable strategy to combat cancer metastasis.