Tumor-derived Jagged1 promotes cancer progression through immune evasion

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint inhibitor (ICI) therapy shows promise in cancer treatment, but response rates vary, particularly in breast cancer.
• Understanding the tumor immune microenvironment is crucial for improving ICI efficacy.

Purpose of the Study:

• To investigate the role of tumor-derived Jagged1 in regulating the tumor immune microenvironment in breast cancer.
• To identify potential therapeutic targets for enhancing ICI therapy in breast cancer.

Main Methods:

• Utilized spontaneous mammary tumor models to study Jagged1 function.
• Analyzed Jagged1-induced Notch signaling pathway activation.
• Assessed the impact of Jagged1 on macrophage recruitment and T cell activity.
• Correlated Jagged1 expression with clinical data in triple-negative breast cancer patients.
• Evaluated the efficacy of combined ICI PD-1 antibody and Notch inhibitor therapy.

Main Results:

• Tumor-derived Jagged1 promotes tumorigenesis and recruits macrophages via Notch activation.
• Macrophages educated by Jagged1 inhibit T cell proliferation and anti-tumor activity.
• High Jagged1 expression in triple-negative breast cancer correlates with increased macrophages and reduced T cell activity.
• Combined ICI PD-1 antibody and Notch inhibitor treatment significantly reduced tumor growth in preclinical models.

Conclusions:

• Jagged1 is a key regulator of the tumor immune microenvironment, promoting immune evasion in breast cancer.
• Jagged1-induced signaling represents a novel pathway for adaptive immune evasion.
• Targeting Jagged1 and Notch signaling offers potential therapeutic strategies to enhance ICI efficacy in breast cancer.