Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells.

Lei Wu, Xudong Liu, Juan Lei, Nan Zhang, Huakan Zhao, Jiangang Zhang, Huan Deng, Yongsheng Li

Journal for immunotherapy of cancer 2023 Dec 06

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Myeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer. The MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs. Here, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+ T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy. These results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Citation

Lei Wu, Xudong Liu, Juan Lei, Nan Zhang, Huakan Zhao, Jiangang Zhang, Huan Deng, Yongsheng Li. Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells. Journal for immunotherapy of cancer. 2023 Dec 06;11(12)