CD45 phosphatase regulates the fate of myeloid cells in tumor microenvironment by inhibiting STAT3 activity

Abstract

Abstract The abnormal differentiation of myeloid cells is one of the key features of altered immune response in cancer. Myeloid derived suppressor cells (MDSC) and tumor associated macrophages (TAM) are the major components of immune suppressive network. MDSC accumulate in large numbers in peripheral lymphoid organs and inside tumors. However, in contrast to peripheral lymphoid organs such as spleen, inside tumors, monocytic MDSC rapidly differentiate to TAM with potent immune suppressive activity. We have demonstrated that this phenomenon is mediated by dramatic down-regulation of STAT3 activity in MDSC in tumor site. In cancer patients, MDSC in tumor site also had substantially lower level of pSTAT3 than MDSC in peripheral blood. These results were unexpected, since high level of STAT3 activity is a hallmark of MDSC present in blood and lymphoid organs. The mice with constitutively active STAT3 had shown the expansion of MDSC and down-regulation of macrophage population in tumor microenvironment, emphasizing the crucial role of STAT3 in myeloid cell differentiation. Hypoxia is an intricate part of tumor microenvironment. The decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. We further demonstrate that the up-regulation of CD45 tyrosine phosphatase activity in MDSC exposed to hypoxia in tumor site was responsible for down-regulation of STAT3 activity. Moreover, the positive regulation of CD45 activity in hypoxia was mediated by the disruption of CD45 protein dimerization via sialylation. This suggests a novel role of STAT3 in the regulation of myeloid cells in tumors with potential implications for therapeutic targeting.