A Mechanistic Study On The Generation And Function Of Monocytic Myeloid-derived Suppressor Cells In Tumor Condition

The process of tumor development and progression is often accompanied with inflammation,and tumor associated inflammation is thought to be a barrier of immunosurveillance.The tumor associated inflammation is found to have functions in multiple aspects during tumor progression,including tumor metastasis,angiogenesis and proliferation of mutant cells.Myeloid-derived suppressor cells(MDSCs)are heterogenerous populations which were abnormally differentiated from hematopoietic stem cells under pathological conditions and could inhibit the immune response.In addition to immunosuppression,MDSCs were also reported to promote angiogenesis and tumor cell arrest in vessels.Monocytic myeloid-derived suppressor cells(mo-MDSCs)is one subset of MDSCs,which is with higher activity of immunosuppression compared with granulocyte myeloid-derived suppressor cells(G-MDSCs),which is the other subset of MDSCs.In this paper,we mainly discussed the cytokines that could induce the expansion of mo-MDSCs under tumor conditions,and how mo-MDSC promotes tumor progression.The expansion and activation of MDSC are influenced by a variety of factors,including tumor cell-secreted factors that could stimulate bone marrow generation and inhibit myeloid cell differentiation,as well as factors secreted by activated T cells and tumor-associated stromal cells which directly activated MDSCs.Firstly,we showed that tumor cell conditioned medium could induce bone marrow cell to differentiate into mo-MDSCs,and cytokine array analysis of the conditioned medium showed that chemokine CXCL1 and CXCL2 could promote the differentiation of bone marrow cells into mo-MDSC.Furthermore,this process was not related to the chemotaxis,proliferation and apoptosis of mo-MDSC.In addition to tumor cells,tumor-infiltrated CD11b~+myeloid cells were another contributor of CXCL1 and CXCL2.We then further explore the function of mo-MDSC in constructing the premetastatic microenvironment.The results showed that mo-MDSCs were recruited into the premetastatic lungs prior to G-MDSC to promote tumor metastasis and increased the capture of tumor cells on blood vessels.Further studies demonstrated that mo-MDSC could secrete cytokines IL-1?and IL-1?acted on vascular endothelial cells to promote the expression of E-selectin in the premetastatic microenvironment,thereby promoting the capture of tumor cells and metastasis.In contrast,when anti-Gr-1 antibody was used to deplete mo-MDSC the expression of E-selectin decreased correspondingly in vivo.We also found that chemokine CCL12 could recruit mo-MDSC to premetastatic microenvironment.When CCL12 was knocked out,the recruitment of mo-MDSC and the expression of E-selectin were both decreased.Our data suggest that CXCL1 and CXCL2 play significant roles in the generation of mo-MDSCs,as well as a novel mechanism of mo-MDSC promoting tumor metastasis.Our results further confirmed the correlation between tumor and inflammation,and may provide a new target for the control of tumor metastasis.