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.