Zikang Xing,Xuewen Li,Zhen Ning Tony He,Xin Fang,Heng Liang,Chunxiang Kuang,Aiying Li,Qing Yang
Glioma is characterized by strong immunosuppression and excessive angiogenesis. Based on existing reports, it can be speculated that the resistance to anti-angiogenic drug vascular endothelial growth factor A (VEGFA) antibody correlates to the induction of novel immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), while IDO1 has also been suggested to be related to tumor angiogenesis. Herein, we aim to clarify the potential role of IDO1 in glioma angiogenesis and the mechanism behind it. Bioinformatic analyses showed that the expressions of IDO1 and angiogenesis markers VEGFA and CD34 were positively correlated and increased with pathological grade in glioma. IDO1-overexpression-derived-tryptophan depletion activated the general control nonderepressible 2 (GCN2) pathway and upregulated VEGFA in glioma cells. The tube formation ability of angiogenesis model cells could be inhibited by IDO1 inhibitors and influenced by the activity and expression of IDO1 in condition medium. A significant increase in serum VEGFA concentration and tumor CD34 expression was observed in IDO1-overexpressing GL261 subcutaneous glioma-bearing mice. IDO1 inhibitor RY103 showed positive anti-tumor efficacy, including the anti-angiogenesis effect and upregulation of natural killer cells in GL261 glioma-bearing mice. As expected, the combination of RY103 and anti-angiogenesis agent sunitinib was proved to be a better therapeutic strategy than either monotherapy.
Li Zhiyao,Fang Mengyuan,Wang Yu,Chen Yunqiu,Liu Yuying,Chen Yijia,Li Xuewen,Meng Fangzhou,Qian Xiaoyang,He Zhen Ning Tony,Yang Qing
Prolonged immunosuppression is a major risk factor for sepsis death. The mechanism of sepsis-associated immunosuppression remains unclear, hindering timely and targeted immunotherapy. The immunomodulatory enzyme, indoleamine-2,3-dioxygenase 1 (IDO1), is overactivated in patients with sepsis; however, its role in sepsis-associated immunosuppression remains unclear. In this study, we defined the time window when cecal ligation puncture (CLP) mice, a gold-standard sepsis model, entered the immunosuppressive state and confirmed elevated IDO1 activity during this phase. The IDO1 inhibitor prevented the occurrence of immunosuppression in CLP mice by decreasing the concentration of interleukin-10 (IL-10), the number of regulatory T cells and myeloid-derived suppressor cells, and increasing the proportion of M1 macrophages, which led to clearance of pathogenic bacteria in the peritoneal cavity. The IDO1 inhibitor enhanced resistance to infection and improved the survival of septic mice during secondary infection with Staphylococcus aureus . Finally, we explored the potential role of IDO1 in macrophages, key participants in the progression of sepsis. IDO1 preferentially promoted IL-10 production in septic macrophages through the aryl hydrocarbon receptor–STAT3 axis. In macrophages, IDO1 inhibited the mammalian target of rapamycin pathway by depleting ambient tryptophan, leading to the downregulation of the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and the metabolic reprogramming mediator hypoxia-inducible factor 1-alpha (HIF-1α). The downregulation of PGC-1α and HIF-1α inhibited mitochondrial biogenesis and glycolysis, respectively, both of which were essential for immune defense. These results demonstrate that IDO1 is a crucial mediator of sepsis-associated immunosuppression, and that targeting IDO1 could serve as a therapeutic strategy for sepsis.
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