Absence of BCAP in myeloid cells abrogates M2 macrophage differentiation and promotes anti-tumor immunity
Kiana Kawarizadeh1,2, Charles N Vallez3,2, Sepideh Aliyazdi4,2
1Molecular Genetics, Biochemistry, and Microbiology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Abstract:
B-cell adaptor for PI3K (BCAP) is a critical signaling adapter that links Toll-like receptors (TLRs) to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and negatively regulates TLR-induced inflammation. BCAP also facilitates transition of macrophages from an inflammatory (M1) to a reparatory (M2) state; however, whether BCAP functions downstream of receptors that directly drive M2 macrophage differentiation is not known. Here, we find that BCAP is essential for M2 differentiation in response to interleukin (IL)-4 and IL-33. BCAP-deficient macrophages displayed an impaired M2 gene program, marked by reduced expression of Arg1, Retnla, and Mgl2. Mechanistically, BCAP enables IL-4-driven PI3K-Akt activation by mediating interactions between p85 and Grb2 without impacting STAT6 function. Strikingly, loss of BCAP, either globally or in myeloid cells, leads to suppressed tumor growth and a shift in tumor-associated macrophages toward a pro-inflammatory state and less exhausted tumor-infiltrating CD8 T cells. These findings present BCAP as a promising therapeutic target for enhancing anti-tumor immunity.
Insights
B-cell adaptor for PI3K (BCAP) is crucial for M2 macrophage differentiation and negatively regulates inflammation. Loss of BCAP suppresses tumor growth by altering macrophage and CD8 T cell states, suggesting BCAP as a therapeutic target.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- B-cell adaptor for PI3K (BCAP) is a known regulator of Toll-like receptor (TLR) signaling and inflammation.
- BCAP's role in M2 macrophage differentiation, particularly downstream of IL-4 and IL-33, was previously unknown.
Purpose of the Study:
- To investigate the role of BCAP in M2 macrophage differentiation.
- To elucidate the molecular mechanisms by which BCAP influences macrophage polarization.
- To assess the impact of BCAP deficiency on tumor immunity.
Main Methods:
- Macrophage differentiation assays using IL-4 and IL-33 stimulation.
- Quantitative PCR to assess M2 gene expression (Arg1, Retnla, Mgl2).
- Western blotting and co-immunoprecipitation to study protein interactions.
- Tumor growth models in mice with global or myeloid-specific BCAP deficiency.
Main Results:
- BCAP is essential for M2 macrophage differentiation induced by IL-4 and IL-33.
- BCAP deficiency impairs M2 gene expression and PI3K-Akt activation.
- BCAP mediates IL-4-induced PI3K-Akt activation via p85-Grb2 interaction, independent of STAT6.
- Loss of BCAP suppresses tumor growth and promotes a pro-inflammatory tumor microenvironment.
Conclusions:
- BCAP is a critical mediator of M2 macrophage polarization.
- BCAP plays a significant role in regulating anti-tumor immunity.
- Targeting BCAP may represent a novel therapeutic strategy for cancer immunotherapy.
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