Abstract
The role of myeloid derived suppressor cells (MDSCs) in promoting tumorigenesis is well-established, and significant effort is being made to further characterize surface markers on MDSCs both for better diagnosis and as potential targets for therapy. Here we show that the B cell receptor adaptor molecule CD79a is unexpectedly expressed on immature bone marrow myeloid cells, and is upregulated on MDSCs generated in multiple different mouse models of metastatic but not non-metastatic cancer. CD79a on MDSCs is upregulated and activated in response to soluble factors secreted by tumor cells. Activation of CD79a on mouse MDSCs, by crosslinking with a specific antibody, maintained their immature phenotype (CD11b+Gr1+), enhanced their migration, increased their suppressive effect on T cell proliferation, and increased secretion of pro-tumorigenic cytokines such as IL-6 and CCL22. Furthermore, crosslinking CD79a on myeloid cells activated signaling through Syk, BLNK, ERK and STAT3 phosphorylation. In vivo, CD79+ myeloid cells showed enhanced ability to promote primary tumor growth and metastasis. Finally we demonstrate that CD79a is upregulated on circulating myeloid cells from lung cancer patients, and that CD79a+ myeloid cells infiltrate human breast tumors. We propose that CD79a plays a functional role in the tumor promoting effects of myeloid cells, and may represent a novel target for cancer therapy.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antibodies / metabolism
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Antigen-Antibody Complex / metabolism
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B-Lymphocytes / metabolism*
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B-Lymphocytes / pathology
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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CD11b Antigen / genetics
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CD11b Antigen / metabolism
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CD79 Antigens / genetics*
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CD79 Antigens / metabolism
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Cell Movement
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Cell Proliferation
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Chemokine CCL22 / metabolism
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Interleukin-6 / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice
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Myeloid Cells / metabolism
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Myeloid Cells / pathology
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Syk Kinase
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies
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Antigen-Antibody Complex
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B cell linker protein
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CD11b Antigen
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CD79 Antigens
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Ccl22 protein, mouse
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Cd79a protein, mouse
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Chemokine CCL22
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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Extracellular Signal-Regulated MAP Kinases