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Targeting interleukin 4 receptor alpha on tumor-associated macrophages reduces the pro-tumor macrophage phenotype
Amber E de Groot1, Kayla V Myers1, Timothy E G Krueger2
1Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins School of Medicine, 600 N. Wolfe St., Baltimore, MD, 21287, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N. Wolfe St., Baltimore, MD, USA.
Abstract:
Tumor-associated macrophages (TAMs) are an abundant tumor-promoting cell type in the tumor microenvironment (TME). Most TAMs exhibit a pro-tumor M2-like phenotype supportive of tumor growth, immune evasion, and metastasis. IL-4 and IL-13 are major cytokines that polarize macrophages to an M2 subset and share a common receptor, IL-4 receptor alpha (IL-4R alpha). Treatment of human ex vivo polarized M2 macrophages and M2 macrophage precursors with IL-4R alpha antagonist antibody Dupilumab (DupixentⓇ) reduces M2 macrophage features, including a shift in cell surface marker protein expression and gene expression. In animal models of prostate cancer, both pharmacologic inhibition of IL-4R alpha and genetic deletion of IL-4R alpha utilizing an Il4ra -/- mouse model result in decreased CD206 on TAMs. These data support IL-4R alpha as a target to reduce the pro-tumor, M2-like macrophage phenotype as a novel adjunct cancer therapy.
Insights
Targeting IL-4 receptor alpha (IL-4R alpha) reduces pro-tumor M2 macrophage features. This approach shows promise for novel adjunct cancer therapies by diminishing tumor growth and metastasis.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Tumor-associated macrophages (TAMs) are key players in the tumor microenvironment (TME), often promoting tumor growth, immune evasion, and metastasis.
- The M2-like phenotype of TAMs is driven by cytokines like IL-4 and IL-13, which signal through the IL-4 receptor alpha (IL-4R alpha).
Purpose of the Study:
- To investigate the therapeutic potential of targeting IL-4R alpha to modulate TAM phenotype.
- To evaluate the efficacy of IL-4R alpha inhibition in reducing pro-tumor M2 macrophage characteristics.
Main Methods:
- Treatment of human M2 macrophages and precursors with Dupilumab, an IL-4R alpha antagonist antibody.
- Pharmacologic inhibition and genetic deletion (Il4ra-/- mice) of IL-4R alpha in prostate cancer models.
- Analysis of M2 macrophage features, including cell surface marker expression (e.g., CD206) and gene expression.
Main Results:
- Dupilumab treatment reduced M2 macrophage features in human cells, altering surface marker and gene expression.
- Inhibition or genetic deletion of IL-4R alpha decreased CD206 expression on TAMs in prostate cancer models.
- These findings indicate that IL-4R alpha blockade effectively reduces the pro-tumor M2 phenotype.
Conclusions:
- IL-4R alpha is a viable therapeutic target for reprogramming TAMs.
- Targeting IL-4R alpha offers a novel strategy for adjunct cancer therapy by reducing pro-tumor macrophage functions.
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