FcγRIIB potentiates differentiation of myeloid-derived suppressor cells to mediate tumor immunoescape

Theranostics. 2022 Jan 1;12(2):842-858. doi: 10.7150/thno.66575. eCollection 2022.


Background: FcγRIIB, 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 FcγRIIB in myeloid-derived suppressor cells (MDSCs) remains unknown. This study aimed to investigate whether and how FcγRIIB 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 FcγRIIB during tumor progression. FcγRIIB-deficient mice, adoptive cell transfer, mRNA-sequencing and flow cytometry analysis were used to assess the role of FcγRIIB on immunosuppressive activity and differentiation of MDSCs. Results: Here we show that FcγRIIB was upregulated in tumor-infiltrated MDSCs. FcγRIIB-deficient mice showed decreased accumulation of MDSCs in the tumor microenvironment (TME) compared with wild-type mice. FcγRIIB 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 FcγRIIB on hematopoietic progenitor cells (HPCs) by activating specificity protein 1 (Sp1), subsequently FcγRIIB 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 FcγRIIB in abnormal differentiation of MDSCs during cancer development and suggest a potential therapeutic target for anti-tumor therapy.

Keywords: Fc gamma receptor IIB; Sp1 signaling; anti-tumor therapy; granulocyte-macrophage colony stimulating factor; immunosuppression; myeloid-derived suppressor cells; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Carcinogenesis*
  • Cell Differentiation*
  • Cell Line, Tumor
  • Drug Delivery Systems
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Derived Suppressor Cells / cytology*
  • Myeloid-Derived Suppressor Cells / immunology
  • Receptors, IgG / deficiency
  • Receptors, IgG / metabolism
  • Receptors, IgG / physiology*
  • Signal Transduction
  • Tumor Escape*


  • Fc gamma receptor IIB
  • Receptors, IgG