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MS4A4A: a novel cell surface marker for M2 macrophages and plasma cells
Ratna Sanyal1, Maria J Polyak1, Jonathan Zuccolo1
1Department of Biochemistry and Molecular Biology, and Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Abstract:
MS4A4A is a member of the membrane-spanning, four domain family, subfamily A (MS4A) that includes CD20 (MS4A1), FcRβ (MS4A2) and Htm4 (MS4A3). Like the first three members of this family, transcription of MS4A4A appears to be limited to hematopoietic cells. To evaluate expression of the MS4A4A protein in hematopoietic cell lineages and subsets we generated monoclonal antibodies against extracellular epitopes for use in flow cytometry. In human peripheral blood we found that MS4A4A is expressed at the plasma membrane in monocytes but not in granulocytes or lymphocytes. In vitro differentiation of monocytes demonstrated that MS4A4A is expressed in immature but not activated dendritic cells, and in macrophages generated in the presence of interleukin-4 ('alternatively activated' or M2 macrophages) but not by interferon-γ and lipopolysaccharide ('classically' activated or M1 macrophages). MS4A4A was expressed in the U937 monocytic cell line only after differentiation. In normal bone marrow, MS4A4A was expressed in mature monocytes but was undetected, or detected at only a low level, in myeloid/monocytic precursors, as well as their malignant counterparts in patients with various subtypes of myeloid leukemia. Although MS4A4A was not expressed in healthy B lymphocytes, it was highly expressed in normal plasma cells, CD138+ cells from multiple myeloma patients, and bone marrow B cells from a patient with mantle cell lymphoma. These findings suggest immunotherapeutic potential for MS4A4A antibodies in targeting alternatively activated macrophages such as tumor-associated macrophages, and in the treatment of multiple myeloma and mantle cell lymphoma.
Insights
The MS4A4A protein is found on monocytes and certain B cells, suggesting potential for antibody-based therapies targeting alternatively activated macrophages and B-cell malignancies like multiple myeloma.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- MS4A4A is a member of the membrane-spanning, four domain family A (MS4A), with restricted expression to hematopoietic cells.
- Understanding MS4A4A protein expression is crucial for exploring its role in immune cell function and potential therapeutic applications.
Purpose of the Study:
- To investigate the expression patterns of the MS4A4A protein across various human hematopoietic cell lineages and subsets.
- To assess the potential of MS4A4A as a therapeutic target in hematological malignancies and inflammatory conditions.
Main Methods:
- Generation of monoclonal antibodies against extracellular MS4A4A epitopes.
- Flow cytometry analysis of MS4A4A expression in peripheral blood, bone marrow, and in vitro differentiated cells.
- Analysis of MS4A4A expression in myeloid leukemia, multiple myeloma, and mantle cell lymphoma patient samples.
Main Results:
- MS4A4A is expressed on the plasma membrane of monocytes, immature dendritic cells, and alternatively activated (M2) macrophages.
- Expression is absent in granulocytes, lymphocytes, classically activated (M1) macrophages, and myeloid precursors.
- MS4A4A is highly expressed on plasma cells, including those from multiple myeloma patients, and in mantle cell lymphoma.
Conclusions:
- MS4A4A is a promising target for immunotherapeutic strategies, particularly for antibody-based treatments.
- Potential applications include targeting tumor-associated macrophages and treating multiple myeloma and mantle cell lymphoma.
