The Role Of SENP1 In Regulation Of MDSCs During Tumorigenesis

SUMOylation is involved in various physiological and pathological processes through modulating target proteins'function.SUMOylation can regulate the proliferation,apoptosis,and invasion ability of tumor cells.Meanwhile,SUMOylation also modulates immuniological reaction.It is well known that immune system has anti-tumor properties.However,this anti-tumor immunity is always suppressed by different factors in tumorigenesis.The Myeloid-derived suppressor cell?MDSC?is one of the factors that suppress the anti-tumor immunity.MDSCs are a group of heterogeneous myeloid cells expanded during tumorigenesis.MDSCs accumulate in peripheral lymphoid organs or solid tumor tissue to exhibit immuno-suppressive activity.The abundance of MDSCs in peripheral blood is a bio-marker for tumor progression or prognosis.We previously showed that sumo specific protease 1 control macrophage polarization through STAT1/STAT3 balance.In this study,we found that MDSCs were systematic expanded in Senp1^-/-bone marrow transplantation chimera mice(Senp1^-/->WT).The tumor growth and tumor metastasis were promoted in Senp1^-/->WT mice compared with that in control mice with several tumor models.Moreover,SENP1deficient MDSCs exhibited much stronger immuno-suppressive activity than SENP1WT MDSCs did.Mechanistically,we found higher STAT3 activation in SENP1deficient MDSCs.The inhibition of STAT3 could reduce the pro-tumorigenesis activity of SENP1 deficient MDSCs.We further determed that CD45 was SUMOylated and SUMOylation could suppress CD45 phosphatase activity in regulation STAT3phosphorylation.SENP1 could de-SUMOylate and activate CD45 activity.In SENP1deficient MDSCs,SUMOylated CD45 accumulated and its phosphatase activity was hampered,which lead to higher STAT3 phosphorylation.We also found that the tumor cell culture medium or tumor challenge could attenuat SENP1 expression in MDSCs.These data reveal a critical role of SENP1 as negative modulator in controlling MDSCs activation in tumorigenesis.