Hypoxia-inducible factor-targeting therapy augmented the sensitivity to programmed death ligand-1 blockade by...

Area of Science:

• Immunology and Cancer Research
• Molecular Oncology
• Tumor Microenvironment

Background:

• Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) offer clinical benefits in advanced cancers.
• Predictive biomarkers for ICI response remain incompletely understood, hindering broader clinical application.
• Tumor-derived CXCL10/11 has been implicated in regulating T cell infiltration and tumor angiogenesis, potentially influencing ICI sensitivity.

Purpose of the Study:

• To investigate the role of tumor-derived CXCL10/11 as a predictive factor for PD-L1 blockade response.
• To elucidate the molecular mechanisms underlying ICI resistance, focusing on interferon-gamma (IFN-γ) inducible genes.
• To evaluate the therapeutic potential of combining HIF1A inhibition with PD-L1 blockade.

Main Methods:

• Gene silencing of tumor-derived CXCL10/11 in mouse models.
• Microarray analysis to compare IFN-γ-inducible gene expression in ICI-sensitive versus ICI-resistant tumor cells.
• Pathway analysis to identify key regulatory signals, including hypoxia-inducible factor 1A (HIF1A).
• In vitro assessment of HIF1A inhibitors (echinomycin, YC-1) on CXCL10/11 expression.
• Combination therapy studies involving PD-L1 blockade and echinomycin in tumor-bearing mice.

Main Results:

• Gene silencing of CXCL10/11 induced resistance to PD-L1 blockade in vivo.
• Microarray and pathway analyses identified HIF1A as a key suppressor of CXCL10/11 expression in ICI-resistant cells.
• HIF1A inhibitors (echinomycin, YC-1) upregulated IFN-γ-induced CXCL10/11 expression in tumor cells.
• Combination therapy with PD-L1 blockade and echinomycin demonstrated synergistic antitumor effects.
• Combination therapy enhanced CD8 T cell infiltration and suppressed tumor angiogenesis.

Conclusions:

• Tumor-derived CXCL10/11 is a critical determinant of response to PD-L1 blockade.
• HIF1A signaling in tumor cells drives ICI resistance by downregulating CXCL10/11.
• Targeting HIF1A in combination with PD-L1 blockade represents a promising strategy to overcome ICI resistance and enhance anti-tumor immunity.