FcγRIIb Regulates The Role Of MDSC Polarization In Tumor Progression

Myeloid-derived suppressor cells(MDSCs)are heterogeneous populations,which include myeloid progenitors and immature myeloid cells that play a key role in tumor-induced immune tolerance.More recent studies have demonstrated that MDSCs are able to polarize from M2(an alternatively activated phenotype)to Ml(a classically activated phenotype)in tumor-bearing mice.MDSCs with M2 like phenotype exhibit pro-tumoral and immunosuppressive activities,while MDSCs with M1 like phenotype exhibit anti-tumoral and immunostimulating activities.Understanding the mechanism of MDSC polarization is prerequisite for their application.Many immune cells express the receptors for the Fc portion of IgG(FcyR).FcγⅡRb is the only inhibitory member of the FcyR family expressed by myeloid cells and B cells.FcγⅡRb can inhibit the humoral immune reaction and maintain the balance of peripheral immune tolerance by regulating the activation threshold of cell response.However,whether MDSCs express FcγⅡRb and what the functions of FcγⅡRb expressed on MDSCs have not been elucidated.Therefore,in this study,we investigate the expression of FcγⅡRb on MDSCs and then we further investigated the effects of FcγⅡRb on the function of MDSCs.1.FcγRⅡIIb deficient MDSCs from tumor-bearing mice exhibit an Ml-like phenotypeFirstly,we analyzed the expression of FcyRIIb on CD11b+Gr-1+ MDSCs from 3LL tumor-bearing mice and found that MDSCs in blood,bone marrow,spleen and tumor tissue expressed FcyRIIb.Then we further investigated the effects of FcγⅡRb on the amplification and function of MDSCs.We found that FcγRⅡb-/-tumor-bearing mice have more CD11b+Gr-1+ MDSCs in spleen.FcyRIIb-/-splenic MDSCs expressed lower quantities of the M2 markers CD206,arginase-1,and IL-10 but higher amounts of the M1 marker CCR7,iNOS,TNF-α and IFN-γ receptor than WT MDSCs,preferentially acquiring an Ml-like phenotype in the spleen.Functionally,the ability of MDSC from FcγRⅡb-/-tumor-bearing mice for inhibiting the proliferation of activated CD4+ T cells significantly decreased compared with that of MDSCs from WT tumor-bearing mice.Furthermore,decreased Treg cell induction was observed when comparing FcγRⅡb-/-to WT splenic MDSCs.In summary of this part of our study,we demonstrate that FcyRIIb deficiency induce MDSCs to polarize from M2 like phenotype to Ml like phenotype.2.The effects of FcyRIIb regulating MDSC polarization on tumor progressionFcγRⅡb-/-MDSCs from tumor-bearing mice were identified to exhibit an M1-like phenotype in part 1.Therefore,we analysed the effect of FcγRⅡb-/-MDSCs on tumour growth in vivo.Mice were subcutaneously transplanted with 3LL tumour cells and then adoptive transfer of WT MDSCs or FcγRⅡb-/-MDSCs.We found that upon adoptive transfer,FcγRⅡb-/-MDSCs significantly retarded the growth of subcutaneous tumors.Then we examined whether FcyRIIb deficiency has any impact on tumor growth.The rate of tumor growth was significantly slower in FcγRⅡb-/-mice compared with WT mice over time and FcyRIIb deficient prolong survival rate in B16F10 and 3LL tumor bearing mice.The mechanisms underlying the retarded tumor growth and enhanced antitumor responses in FcγRⅡb-/-tumor-bearing mice need to be elucidated in the future.Together,these data suggest that FcγRⅡb deficiency results in enhanced antitumor responses and the results obtained from this project might be helpful to better understand the mechanisms underlying MDSC polarization and the pivotal role for FcγRⅡb in regulating immune response,and open novel avenues for therapeutic strategies.