Functional And Mechanistic Characterization Of CXCR2 In Promoting Myelogenous Progenitor Cells Differentiation Into Mo-MDSCs Under Tumor-bearing Conditions

Malignant tumor is a serious threat to human health and has become the main cause of human death.The key reason why the body’s immune system failed to eliminate the tumor is that the tumor cells reprogrammed the immune system,causing the tumor to evade immune destruction.Evading immune destruction is the effect of the interaction between tumor cells and the immune system.Due to the existence of tumor cells in the body,not only the immune system has the protective function of resisting tumor,but also tumor cells reduce the antigen specificity of surface through the derivation of immunosuppressive factors by tumor cells.More importantly,tumor cells escape immune destruction by inhibiting the activity of immune cells.The factors released by tumor cells work together with pro-inflammatory factors to make hematopoietic stem cells differentiate abnormally and accumu Late myeloid derived immunosuppressive cells(MDSCs).MDSCs promote tumor progression by directly inhibiting the function of effector immune cells,and also regu Late the occurrence and development of tumors by participating in the construction of tumor pre-metastasis microenvironment,tumor angiogenesis and tumor metastasis.As one of the subgroups of MDSC,the number of monocytic myeloid immunosuppressive cells(mo-MDSCs)are less than granu Locytic MDSCs(G-MDSCs),but their immunosuppressive activity is more prominent.We have found that CXCL1 and CXCL2 promoted the differentiation of myeloid progenitor cells into mo-MDSC.In this paper,the mechanism of the abnormal differentiation of myeloid progenitor cells into mo-MDSC under tumor environment was discussed in depth.Here we found that: 1)granu Locyte and macrophage progenitor cells(GMPs)expressed CXCR2.CXCR2 on GMPs was activated by CXCL1 and CXCL2 secreted by tumor and its stromal cells.GMPs gave rise to more MDPs,then MDPs generated mo-MDSCs.2)Futher study demonstrated that activated CXCR2 inhibited the expression of SAP18 that has been identified as a subunit of the transcriptional corepressor,Sin3A-HDAC complex.SAP18 binds to the regu Latory sequences of HRAS and PI3Kγ,which enhances the binding of m Sin3 A to the promoter of HRAS and PI3Kγ to inhibit the transcription of HRAS and PI3Kγ.Inversely,the inhibition expression of SAP18 promoted the expression of HRAS and PI3Kγ which subsequently activates the ERK/STAT3 signaling pathway.Phosphorylated STAT3 promoted the transcription of transcription factors associated with mo-MDSC differentiation after nuclear entry,then mo-MDSCs accumu Lated.3)under tumor conditions,CXCR2 activation resulted in increasing mi R-449 c expression to degrade STAT6 that promoted the generation of moMDSCs.In this case,we found a new regu Latory mechanism of the abnormal differentiation of myeloid progenitor cells into mo-MDSC under tumor environment.It is that the increased binds of CXCL1 or CXCL2 to CXCR2 leads to reduced SAP18 expression under tumor conditions,which subsequently activates the ERK/STAT3 signaling pathway or increases mi R-449 c degrading STAT6 to promote mo-MDSCs accumu Lation.This study reveales a new role of CXCR2 in regu Lating differentiation in addition to chemotaxis,and clearly indicates the stage of myeloid progenitor cells had abnormal differentiation in the tumor environment.Therefore,this study deepens the understanding of the function of chemokine receptor and the relationship between tumor and immune editing,which may provide new targets for tumor immunotherapy.