Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF

Abstract

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that accumulate in tumor-bearing hosts. Since MDSCs suppress anti-tumor immunity and promote tumor progression, they are promising targets for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF) is an agent used for the treatment of chemotherapy-induced febrile neutropenia (FN) in patients with cancer. However, several reports have revealed that G-CSF plays crucial immune-related adverse roles in tumor progression through MDSCs. In this study, we showed that MDSCs differentiated in the presence of G-CSF in vitro exhibited enhanced proliferation and immunosuppressive activity compared to those differentiated without G-CSF. RNA sequencing analysis demonstrated that G-CSF enhanced the immunosuppressive function of MDSCs by upregulating gamma-glutamyltransferase (GGT) 1. Moreover, in the EL4 lymphoma-bearing neutropenic mouse model, administration of recombinant G-CSF increased the number of MDSCs and attenuated the anti-cancer effect of chemotherapy. We showed that the combination of GGsTop, a GGT inhibitor, could prevent G-CSF-induced tumor growth, without affecting the promotion of myelopoiesis by G-CSF. These results suggest that targeting GGT1 can mitigate G-CSF-induced enhanced immunosuppressive functions of MDSCs and can eliminate the tumor-promoting effect of G-CSF. Furthermore, GGsTop could be an attractive combination agent during G-CSF treatment for FN in patients with cancer.

Alkaline phosphatase combined with γ-glutamyl transferase is an independent predictor of prognosis of hepatocellular carcinoma patients receiving programmed death-1 inhibitors

“…GGT increases the level of intracellular glutathione, which can promote tumor cells to maintain balance in reactive oxygen species and avoid cell death through redox pathways during pro-oxidant therapy ( 33 ), GGT-positive tumors possess stronger proliferative ability and drug resistance ( 34 , 35 ). Researchers have demonstrated that granulocyte colony-stimulating factor (G-CSF) upregulates GGT1 and enhances the immunosuppressive function of myeloid-derived suppressor cells, and GGT inhibitors can alleviate tumor immunosuppression and the tumor-promoting effect of G-CSF ( 36 ). Alkaline phosphatase is ubiquitous expressed in human body, which has four types: intestinal ALP, placental ALP, germ cell ALP and single tissue non-specific ALP ( 37 ).…”

Myeloid-derived suppressor cells exacerbate poly(I:C)-induced lung inflammation in mice with renal injury and older mice

“…To verify the direct effect of MDSCs on poly(I:C)-induced lung inflammation, in vitro MDSCs were adoptively transferred into mice in an intravenous manner and the consequences of inflammation were studied. In vitro MDSCs were differentiated from BM cells with GM-CSF stimulation, as described previously (CD11b + Gr-1 + MDSC purity over 90%, Figure S5A ) ( 35 , 36 ). These cells displayed higher Arg1 , Nos2 , and Cybb expression than BM cells ( Figure S5B ) and potently inhibited CD8 + T-cell proliferation ( Figure S5C ).…”

Modified method for differentiation of myeloid-derived suppressor cells in vitro enhances immunosuppressive ability via glutathione metabolism

“…The analysis of gene expression profiles showed that glutathione metabolism was the pathway responsible for the enhanced immunosuppressive ability of 6G − BM-MDSC. We previously showed that glutamate, one of the metabolites of glutathione, would enhance the immunosuppressive function of MDSCs [ 14 ]. In addition, we found that glutamate signaling through metabotropic glutamate receptor 2/3 enhances the immunosuppressive ability of MDSCs [ 30 ].…”

“…Most importantly, they listed some clinical cases that used GM-CSF to rescue tumor therapy-induced neutropenia. We previously reported that G-CSF, which is used for the prevention and therapy for neutropenia, enhanced the immunosuppressive activity of MDSCs through the glutathione degradation pathway, leading to tumor progression [ 14 ]; therefore, GM-CSF might also do so. Although further in vivo cancer model studies are needed, our findings indicated that such GM-CSF treatment might lead to the differentiation of stronger immunosuppressive MDSCs.…”

“…Studies have reported that several inflammatory factors are involved in the differentiation, proliferation, and immunosuppressive function of MDSCs; for instance, cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) induced MDSC differentiation [ 7 , 13 , 14 ]. However, little is known about the MDSC differentiation pathway and its mechanism.…”