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Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis
Sabina Kaczanowska1, Daniel W Beury1, Vishaka Gopalan2
1Tumor Microenvironment and Metastasis Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Abstract:
Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.
Insights
Targeting myeloid cell immune suppression in the pre-metastatic niche with engineered cells delivering IL-12 reduces tumor burden and improves survival in mice. This approach rebalances the metastatic microenvironment, offering a novel cancer therapy strategy.
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.
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