Targeting CSF1R in myeloid-derived suppressor cells: insights into its immunomodulatory functions in colorectal...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Myeloid-derived suppressor cells (MDSCs) are key mediators of immune suppression in colorectal cancer (CRC).
• The Colony-Stimulating Factor 1 Receptor (CSF1R) signaling pathway is implicated in MDSC function and tumor progression.
• Understanding the precise role of CSF1R in MDSC-mediated immune suppression is crucial for developing novel cancer therapies.

Purpose of the Study:

• To investigate the role of CSF1R in MDSC-mediated immune suppression within the CRC microenvironment.
• To elucidate the involvement of the JAK/STAT3 signaling axis in CSF1R-regulated MDSC functions.
• To evaluate the therapeutic potential of combining CSF1R inhibition with anti-PD-1 immunotherapy in a preclinical CRC model.

Main Methods:

• Single-cell and bulk RNA sequencing were employed to identify MDSC-related genes and profile gene expression in murine CRC tumors.
• Lipid-based nanocarriers delivering CSF1R siRNA (LNCs@CSF1R siRNA) were synthesized and characterized for targeted delivery and inhibition.
• Flow cytometry, Western blotting, and metabolic assays were used to assess MDSC populations, surface markers, signaling pathway activation (JAK/STAT3), and metabolic profiles (glucose and fatty acid uptake).
• The therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a syngeneic murine CRC model.

Main Results:

• CSF1R was identified as a significant regulator of MDSC-mediated immune suppression in CRC.
• LNCs@CSF1R siRNA effectively targeted MDSCs and inhibited CSF1R, leading to reduced STAT3 activation via the JAK/STAT3 pathway.
• CSF1R inhibition modulated MDSC fatty acid metabolism and immune suppressive functions, which could be rescued by Colivelin.
• Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly suppressed tumor growth and reduced MDSC infiltration in CRC tumors.

Conclusions:

• The CSF1R signaling axis, particularly through JAK/STAT3, plays a critical role in regulating MDSC-mediated immune suppression and fatty acid metabolism in CRC.
• Combination therapy utilizing LNCs@CSF1R siRNA and anti-PD-1 demonstrates enhanced therapeutic efficacy in a preclinical CRC model.
• These findings provide a strong rationale for the clinical investigation of combined CSF1R inhibition and immunotherapy in colorectal cancer patients.