Tumor-derived GCSF Alters Tumor and Systemic Immune System Cell Subset Composition and Signaling

Area of Science:

• Immunology
• Cancer Biology
• Oncology

Background:

• Immunotherapies like checkpoint blockade and T-cell therapy show promise but have limited response rates.
• Tumor-derived factors can impair phagocyte function, compromising anti-tumor immunity.
• Granulocyte-colony stimulating factor (G-CSF) is implicated in altering immune cell dynamics within the tumor microenvironment.

Purpose of the Study:

• To investigate the impact of tumor-derived G-CSF on myeloid cell populations and immunotherapy efficacy.
• To determine if G-CSF blockade can restore anti-tumor immunity and improve treatment outcomes.
• To correlate G-CSF and myeloid-derived suppressor cell (MDSC) levels with patient survival in colorectal cancer.

Main Methods:

• Utilized Cytometry by Time-of-Flight (CTOF) to analyze immune cell subsets in tumor-bearing mice.
• Performed in vitro bone marrow cultures with G-CSF-conditioned media.
• Administered anti-G-CSF neutralizing antibodies in spontaneous mouse cancer models.
• Analyzed human colorectal cancer patient gene expression data.

Main Results:

• Tumor-derived G-CSF induced significant myeloid cell perturbations, including increased immature neutrophils/myeloid-derived suppressor cells (Neut/MDSCs) and altered dendritic cell (DC) development.
• G-CSF impaired T-cell adoptive cell therapy efficacy, increased tumor volume, and reduced survival in mice.
• Anti-G-CSF antibody treatment reduced Neut/MDSCs, normalized immune cell composition, and diminished tumor burden.
• Human data showed a correlation between low G-CSF/Neut/MDSC gene expression and improved survival.

Conclusions:

• Tumor-derived G-CSF dysregulates myeloid cell populations and suppresses anti-tumor immunity, negatively impacting immunotherapy effectiveness.
• G-CSF blockade represents a promising strategy to restore immune homeostasis and enhance cancer immunotherapy.
• Targeting G-CSF may synergize with existing immunotherapies for cancers overexpressing this cytokine.