SDCBP modulates tumor microenvironment, tumor progression and anti-PD1 efficacy in colorectal cancer

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Anti-programmed cell death 1 (aPD1) therapy shows limited efficacy in colorectal cancer (CRC).
• Syndecan binding protein (SDCBP) is crucial for cellular functions and implicated in cancer progression.
• High SDCBP expression correlates with poor response to immunotherapy and reduced disease-free survival in CRC patients.

Purpose of the Study:

• To investigate the role of SDCBP in colorectal cancer progression, immunotherapy response, and the tumor microenvironment (TME).
• To evaluate the therapeutic potential of inhibiting SDCBP in combination with aPD1 therapy for CRC.

Main Methods:

• Investigated SDCBP expression in CRC patients and its correlation with clinical outcomes.
• Utilized shRNA and zinc pyrithione (ZnPT) to inhibit SDCBP in mouse xenograft and liver metastasis models.
• Analyzed changes in the TME, including macrophage polarization (M1/M2), following ZnPT treatment.
• Employed co-culture systems to confirm SDCBP's effect on macrophage repolarization.

Main Results:

• High SDCBP expression was linked to immunotherapy non-response and poorer disease-free survival in CRC.
• SDCBP inhibition (shRNA or ZnPT) reduced CRC cell proliferation and metastasis.
• Combined SDCBP inhibition and aPD1 therapy significantly enhanced treatment efficacy in preclinical models.
• ZnPT treatment shifted the TME by decreasing M2 macrophages and increasing M1 macrophages, promoting M2 to M1 repolarization.

Conclusions:

• SDCBP promotes colorectal cancer proliferation, metastasis, and resistance to immunotherapy.
• Zinc pyrithione (ZnPT) is an effective inhibitor of SDCBP.
• Combining ZnPT with aPD1 therapy holds significant potential for improving colorectal cancer treatment outcomes.