GM-CSF Promotes Neutrophil PD-L1 Expression Through the VEGFR-2/STAT6/CSF2 Signaling Axis in Oral Squamous Cell...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Oral squamous cell carcinoma (OSCC) exhibits poor response to anti-PD-1 immunotherapy.
• VEGFR-2 inhibition combined with anti-PD-1 shows promise, suggesting a VEGFR-2-mediated immune regulation.

Purpose of the Study:

• To elucidate the mechanism by which VEGFR-2 signaling influences the tumor immune microenvironment in OSCC.
• To identify specific cell populations and signaling pathways involved in VEGFR-2-dependent immune suppression.

Main Methods:

• Multiplex immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and flow cytometry were employed.
• Investigated the role of VEGFR-2, GM-CSF, and PD-L1 in neutrophils within OSCC tumors.
• Utilized in vivo models to assess the efficacy of VEGFR-2 inhibition and GM-CSF neutralization.

Main Results:

• Identified PD-L1-expressing CD66b+ neutrophils as a key immunosuppressive population in VEGFR-2-high OSCC.
• Demonstrated that VEGFR-2-overexpressing OSCC cells secrete GM-CSF, upregulating PD-L1 on neutrophils via STAT6 and STAT5 signaling.
• Showed that these PD-L1+ neutrophils suppress CD8+ T-cell function and that targeting this axis improves anti-PD-1 therapy response.

Conclusions:

• Uncovered a novel VEGFR-2/STAT6/CSF2 axis driving neutrophil-mediated immune suppression in OSCC.
• This axis promotes tumor immune evasion and limits anti-PD-1 efficacy.
• Targeting the VEGFR-2/GM-CSF-neutrophil pathway offers a promising strategy to enhance anti-PD-1 immunotherapy for OSCC.