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G-CSF Is a Novel Mediator of T-Cell Suppression and an Immunotherapeutic Target for Women with Colon Cancer
Anita L Ray1, Apryl S Saunders1, Robert A Nofchissey1
1Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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+ T cells and IFNγ responses to chronic ex vivo G-CSF. An immunocompetent mouse model of peritoneal metastasis (MC38 cells in C57Bl/6J) was used to determine the effects of G-CSF inhibition (αG-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 IFNγ production. Treatment with αG-CSF shifts both the adaptive and innate compartments of the TME and increases survival (HR, 0.46; P = 0.0237) and tumor T-cell infiltration, activity, and IFNγ 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 immunotherapeutic target against colon cancer with greater potential benefit in women.
Insights
Granulocyte-colony stimulating factor (G-CSF) promotes colon cancer. Inhibiting G-CSF may be an effective immunotherapy, particularly for women, by improving survival and anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Cancer Therapeutics
Background:
- Granulocyte-colony stimulating factor (G-CSF) is implicated in enhancing colon cancer development.
- Understanding G-CSF signaling in human colon cancers is crucial for developing targeted therapies.
Purpose of the Study:
- To determine the prevalence and effects of elevated G-CSF signaling in human colon cancers.
- To investigate G-CSF inhibition as an immunotherapeutic strategy for metastatic colon cancer.
Main Methods:
- Human colon cancer samples and patient sera were analyzed for G-CSF and G-CSF receptor (G-CSFR) levels.
- Peripheral blood mononuclear cells assessed T cell G-CSFR expression and IFNγ responses.
- An immunocompetent mouse model evaluated the impact of G-CSF inhibition (αG-CSF) on survival and the tumor microenvironment (TME).
Main Results:
- Elevated G-CSF and G-CSFR levels were observed in human colon cancer tissues compared to normal tissues.
- High serum G-CSF correlated with poor prognostic markers (VEGF, IL6) and increased G-CSFR+ T cells.
- αG-CSF treatment improved survival, increased T cell infiltration and activity, and enhanced IFNγ response in the TME, with notable effects in female mice.
Conclusions:
- G-CSF represents a viable immunotherapeutic target for colon cancer.
- G-CSF inhibition demonstrates significant potential for improving outcomes in colon cancer patients, especially women.
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