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

• 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 Elsevier Inc 16.02.2016; Elsevier Limited
• Subjects: Animals; Cell Differentiation; Cell Movement; Cells, Cultured; Deoxyribonucleic acid; Dimerization; DNA; Experiments; Female; Flow cytometry; Gene expression; Hypoxia; Hypoxia - immunology; Kinases; Leukocyte Common Antigens - genetics; Leukocyte Common Antigens - metabolism; Macrophages - immunology; Melanoma; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells - immunology; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Proteins; Rodents; Sialic Acids - metabolism; Software; Spleen; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumor Microenvironment; Tumors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.01.014

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. [Display omitted] •MDSC differentiation to TAM in hypoxic environment is regulated by STAT3 activity•STAT3 inhibition in MDSC was caused by upregulation of CD45 phosphatase activity•Activation of CD45 phosphatase was mediated by sialic acid•Degradation of sialic acid sensitized tumor myeloid cells to STAT3 inhibitor Gabrilovich and colleagues demonstrate that tumor monocytic cells rapidly differentiate to macrophages due to hypoxia inducible decrease of STAT3 activity. Inhibition of CD45 phosphatase mediated by sialic acid was responsible for this effect. Degradation of sialic acid sensitized tumor myeloid cells to STAT3 inhibitor, resulting in potent antitumor effect.