Gasdermin D restricts anti-tumor immunity during PD-L1 checkpoint blockade

Area of Science:

• Immunology
• Cancer Biology
• Molecular Medicine

Background:

• Tumor microenvironments (TMEs) involve complex immune cell interactions influencing cancer progression and immunotherapy outcomes.
• Caspase-activated gasdermins, like gasdermin D (GSDMD), are known to induce cell death and modulate anti-tumor immunity.
• The specific role of pyroptosis within immune cells in the TME remains largely undefined.

Purpose of the Study:

• To investigate the function of gasdermin D (GSDMD) in immune cells within the tumor microenvironment (TME).
• To determine the impact of GSDMD expression in antigen-presenting cells (APCs) on anti-tumor immunity, particularly during PD-L1 inhibition.
• To explore the potential of combining GSDMD and PD-L1 inhibition as a therapeutic strategy for cancer immunotherapy.

Main Methods:

• Conditional deletion of GSDMD in TME APCs.
• Analysis of immune cell activation, including CD8+ T cell responses.
• Assessment of interferon-stimulated genes (ISGs) and cGAS-dependent pathways.
• Pharmacological inhibition of GSDMD-mediated pyroptosis and PD-L1.

Main Results:

• GSDMD is highly expressed in TME APCs and correlates with immune checkpoint signatures.
• Conditional deletion of GSDMD in TME APCs was found to restrict anti-tumor immunity during PD-L1 inhibition.
• Loss of GSDMD in APCs led to enhanced interferon-stimulated genes (ISGs) and promoted CD8+ T cell activation via a cGAS-dependent mechanism.
• Combined pharmacological inhibition of GSDMD-mediated pyroptosis and PD-L1 significantly improved anti-tumor immunity.

Conclusions:

• GSDMD in TME APCs acts as a negative regulator of anti-tumor immunity.
• Targeting GSDMD-mediated pyroptosis in conjunction with PD-L1 blockade represents a promising therapeutic avenue for enhancing cancer immunotherapy.