Fc gamma RIIB potentiates differentiation of myeloid-derived suppressor cells to mediate tumor immunoescape

Background: Fc gamma RIIB, the sole inhibitory receptor of the Fc gamma receptor family, plays pivotal roles in innate and adaptive immune responses. However, the expression and function of Fc gamma RIIB in myeloid-derived suppressor cells (MDSCs) remains unknown. This study aimed to investigate whether and how Fc gamma RIIB regulates the immunosuppressive activity of MDSCs during cancer development. Methods: The MC38 and B16-F10 tumor-bearing mouse models were established to investigate the role of Fc gamma RIIB during tumor progression. Fc gamma RIIB-deficient mice, adoptive cell transfer, mRNA-sequencing and flow cytometry analysis were used to assess the role of Fc gamma RIIB on immunosuppressive activity and differentiation of Results: Here we show that Fc gamma RIIB was upregulated in tumor-infiltrated MDSCs. Fc gamma RIIB-deficient mice showed decreased accumulation of MDSCs in the tumor microenvironment (TME) compared with wild-type mice. Fc gamma RIIB was required for the differentiation and immunosuppressive activity of MDSCs. Mechanistically, tumor cell-derived granulocyte-macrophage colony stimulating factor (GM-CSF) increased the expression of Fc gamma RIIB on hematopoietic progenitor cells (HPCs) by activating specificity protein 1 (Sp1), subsequently Fc gamma RIIB promoted the generation of MDSCs from HPCs via Stat3 signaling. Furthermore, blockade of Sp1 dampened MDSC differentiation and infiltration in the TME and enhanced the anti-tumor therapeutic efficacy of gemcitabine. Conclusion: These results uncover an unrecognized regulatory role of the Fc gamma RIIB in abnormal differentiation of MDSCs during cancer development and suggest a potential therapeutic target for anti-tumor therapy.