Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy

Area of Science:

• Immunology
• Oncology
• Inflammation research

Background:

• Interleukin-38 (IL-38) is identified as a negative regulator of auto-inflammation.
• The complex relationship between anti-tumor immunity and auto-inflammation suggests IL-38 blockade could enhance tumor immune control.

Purpose of the Study:

• To investigate the potential of blocking IL-38 to enhance anti-tumor immunity.
• To explore the mechanisms by which IL-38 blockade affects the tumor microenvironment and immune cell composition.

Main Methods:

• Utilized a transgenic mammary carcinoma model to assess IL-38 blockade effects.
• Employed neutralizing antibodies for IL-38 blockade, alone and with chemotherapy.
• Analyzed immune cell infiltration, signaling pathways (γδ T-cell receptor, Notch), and gene expression (RNA sequencing).

Main Results:

• IL-38 blockade, via genetic ablation or antibody neutralization, reduced tumor growth and improved chemotherapy outcomes.
• Augmented tumor infiltration of γδ T cells and CD8+ T cells was observed, with γδ T cells crucial for CD8+ T cell recruitment.
• γδ T cells attracted cDC1 via XCL1, which then activated CD8+ T cells through the Notch pathway; IL-38 negatively correlated with these immune components and patient survival.

Conclusions:

• Interfering with IL-38 significantly boosts anti-tumor immunity.
• This strategy is effective even in tumors with a poor immune response (immunologically cold tumors).