CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation

Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by...

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Published in:Immunity (Cambridge, Mass.) Vol. 44; no. 2; pp. 303 - 315
Main Authors: Kumar, Vinit, Cheng, Pingyan, Condamine, Thomas, Mony, Sridevi, Languino, Lucia R, McCaffrey, Judith C, Hockstein, Neil, Guarino, Michael, Masters, Gregory, Penman, Emily, Denstman, Fred, Xu, Xiaowei, Altieri, Dario C, Du, Hong, Yan, Cong, Gabrilovich, Dmitry I
Format: Journal Article
Language:English
Published: United States 16.02.2016
Subjects:
Animals
Cell Differentiation
Cell Movement
Cells, Cultured
Dimerization
Female
Hypoxia - immunology
Leukocyte Common Antigens - genetics
Leukocyte Common Antigens - metabolism
Macrophages - immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Myeloid Cells - immunology
Phosphoric Monoester Hydrolases - genetics
Phosphoric Monoester Hydrolases - metabolism
Sialic Acids - metabolism
STAT3 Transcription Factor - genetics
STAT3 Transcription Factor - metabolism
Tumor Microenvironment
ISSN:1097-4180
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Summary:Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy.
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ISSN:1097-4180
DOI:10.1016/j.immuni.2016.01.014