CXCR2 inhibition enables NASH-HCC immunotherapy

Area of Science:

• Oncology
• Immunology
• Hepatology

Background:

• Hepatocellular carcinoma (HCC) is increasingly linked to non-alcoholic steatohepatitis (NASH).
• NASH-HCC may exhibit reduced sensitivity to conventional immune checkpoint inhibition (ICI).
• Neutrophils play a complex role in the tumor microenvironment.

Purpose of the Study:

• To investigate if targeting neutrophils via a CXCR2 inhibitor can sensitize NASH-HCC to ICI therapy.
• To characterize the immune microenvironment changes induced by combination therapy.

Main Methods:

• Analysis of neutrophil infiltration in human NASH-HCC and mouse models.
• Intervention with anti-PD1 and/or a CXCR2 inhibitor in murine NASH-HCC models.
• Characterization of the tumor immune microenvironment using imaging mass cytometry, RNA-seq, and flow cytometry.

Main Results:

• High CXCR2 expression on neutrophils in human NASH-HCC.
• Combination of CXCR2 antagonist and anti-PD1 suppressed tumor burden and improved survival in NASH-HCC models.
• Therapy led to reprogramming of tumor-associated neutrophils (TANs) into an anti-tumor phenotype, enhancing CD8+ T cell activity and anti-tumor immunity.

Conclusions:

• CXCR2 inhibition effectively reprograms the tumor immune microenvironment in NASH-HCC.
• This reprogramming potentiates the efficacy of immune checkpoint inhibition therapy for NASH-HCC.