Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor-based immunotherapy

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• NADPH oxidases (NOX) generate reactive oxygen species, influencing physiological and pathological processes.
• NOX1 is upregulated in colon cancer, promoting tumor progression.
• Targeting NOX1 presents a potential anticancer strategy.

Purpose of the Study:

• To evaluate the efficacy of the NOX1-selective inhibitor GKT771 in colorectal cancer models.
• To investigate the role of the host immune system and NOX1 in mediating GKT771's antitumor effects.
• To assess the combination therapy of GKT771 with anti-PD1 checkpoint inhibition.

Main Methods:

• Tumor xenografts were established in immunocompetent, immunodeficient, and NOX1-deficient mice.
• Mice were treated with GKT771, an anti-PD1 antibody, or a combination thereof.
• Tumor growth, lymphangiogenesis, angiogenesis, and immune cell infiltration were analyzed.

Main Results:

• GKT771 significantly reduced tumor growth, lymphangiogenesis, and angiogenesis.
• GKT771 treatment enhanced the recruitment of proinflammatory macrophages and natural killer T lymphocytes.
• GKT771's efficacy was dependent on an intact host immune system; it was ineffective in immunodeficient mice.
• Combined GKT771 and anti-PD1 therapy demonstrated superior inhibition of colon carcinoma growth compared to monotherapy.

Conclusions:

• NOX1 inhibition by GKT771 suppresses colorectal tumor growth via anti-angiogenesis and immune cell recruitment.
• The therapeutic benefit of GKT771 relies on a functional immune system.
• Combining NOX1 inhibition with checkpoint blockade offers a promising strategy for colorectal cancer treatment.