Systemic inflammatory responses including
thrombocytosis,
leukocytosis, or neutrophilia have gained attention as prognostic indicators in patients with various solid
malignancies.current study, we aimed to investigate the clinical implications and underlying biological mechanism of the systemic inflammatory response in
endometrial cancer. Clinical data from 900 patients with
endometrial cancer were analyzed to investigate the association between pretreatment
leukocytosis,
thrombocytosis, and treatment outcome. Clinical samples,
endometrial cancer cell lines, and a mouse model of
endometrial cancer were used to examine the mechanisms responsible for systemic inflammatory response in
endometrial cancer, focusing on the role of
tumor-derived
granulocyte colony-stimulating factor (
G-CSF) and MDSCs. Then, we showed that pretreatment concurrent
leukocytosis and
thrombocytosis is associated with significantly shorter survival and decreased chemosensitivity among patients with
endometrial cancer. In vitro and in vivo experiments revealed that
tumor-derived
G-CSF and
G-CSF-mediated
IL-6 production from the tumor microenvironment are involved in the development of
leukocytosis and
thrombocytosis in patients with
endometrial cancer. Moreover, increased
tumor-infiltrating MDSCs induced by
tumor-derived
G-CSF, MDSC-mediated T cell suppression, and MDSC-mediated cancer stem cell induction are responsible for progression and chemoresistance in this type of
endometrial cancer. MDSC depletion using an anti-Gr-1
neutralizing antibody or inhibition of MDSC activity by
celecoxib inhibited
tumor growth and enhanced chemosensitivity in
endometrial cancer displaying concurrent
leukocytosis and
thrombocytosis. In conclusion, Pretreatment concurrent
leukocytosis and
thrombocytosis are associated with significantly shorter survival and decreased chemosensitivity among patients with
endometrial cancer. Combining MDSC-targeting treatments with current standard
chemotherapies might have therapeutic efficacy for these patients.