G-CSF Is a Novel Mediator of T-Cell Suppression and an Immunotherapeutic Target for Women with Colon Cancer

Purpose: G-CSF enhances colon cancer development. This study defines the prevalence and effects of increased G-CSF signaling in human colon cancers and investigates G-CSF inhibition as an immunotherapeutic strategy against metastatic colon cancer. Experimental Design: Patient samples were used to evaluate G-CSF and G-CSF receptor (G-CSFR) levels by IHC with sera used to measure G-CSF levels. Peripheral blood mononuclear cells were used to assess the rate of G-CSFR thorn T cells and IFNy responses to chronic ex vivo G-CSF. An immunocompetent mouse model of peritoneal metastasis (MC38 cells in C57Bl/6J) was used to deter-mine the effects of G-CSF inhibition (aG-CSF) on survival and the tumor microenvironment (TME) with flow and mass cytometry.Results: In human colon cancer samples, the levels of G-CSF and G-CSFR are higher compared to normal colon tissues from the same patient. High patient serum G-CSF is associated with increases in markers of poor prognosis, (e.g., VEGF, IL6). Circulating T cells from patients express G-CSFR at double the rate of T cells from controls. Prolonged G-CSF exposure decreases T cell IFNy production. Treatment with aG-CSF shifts both the adaptive and innate compartments of the TME and increases survival (HR, 0.46; P 1/4 0.0237) and tumor T-cell infiltration, activity, and IFNy response with greater effects in female mice. There is a negative correlation between serum G-CSF levels and tumor-infiltrating T cells in patient samples from women.Conclusions: These findings support G-CSF as an immunother-apeutic target against colon cancer with greater potential benefit in women.