Targeting gamma-glutamyltransferase 1 on myeloid-derived suppressor cells prevents tumor progression caused by G-CSF in neutropenic mouse model

Myeloid-derived suppressor cells (MDSCs) are one of the 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 for the treatment of chemotherapy-induced febrile neutropenia in patients with cancer. However, several reports reveal that G-CSF would play 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 the enhanced proliferation and immunosuppressive activity compared with those differentiated without G-CSF. RNA-seq analysis demonstrated that G-CSF enhanced the immunosuppressive function of MDSCs through the upregulation of gamma-glutamyltransferase (GGT) 1. Moreover, in the EL4 lymphoma-bearing neutropenic mouse model, the administration of recombinant G-CSF increased MDSCs and attenuated anti-cancer effect of chemotherapy. We showed that the combination of GGsTop, a GGT inhibitor, with G-CSF could prevent tumor growth caused by G-CSF, without affecting the promoting myelopoiesis by G-CSF. These results suggest that targeting GGT1 on MDSCs can eliminate the effect of G-CSF in promoting tumor growth. GGsTop could be an attractive combination agent when receiving G-CSF treatment for febrile neutropenia in patients with cancer. Overall design: We performed an RNA-seq analysis, comparing gene expression profile of in vitro MDSCs differentiated with or without G-CSF.