iNOS is a key mediator of anti-PD-1 melanoma therapy response

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Historically, inducible nitric oxide synthase (iNOS) and nitric oxide (NO) were associated with poor melanoma prognosis.
• Emerging evidence suggests NO plays a supportive role in anti-tumor immunity.
• This study investigates the role of iNOS in modulating anti-PD-1 therapy effectiveness, focusing on interferon signaling pathways.

Purpose of the Study:

• To determine the necessity of iNOS-derived NO for anti-PD-1 immunotherapy efficacy in melanoma.
• To elucidate the mechanisms by which iNOS influences anti-tumor immune responses and interferon signaling.
• To explore the potential of NO-producing immune cells as biomarkers for treatment response in melanoma patients.

Main Methods:

• Comparison of B16-D5 melanoma tumor growth and anti-PD-1 response in wild-type and iNOS knockout mice.
• Assessment of NO production, PD-L1 expression, and interferon-related gene activation using flow cytometry and RNA sequencing.
• In vitro studies with NO donors on melanoma cells and analysis of patient immune cells correlating with progression-free survival.

Main Results:

• iNOS knockout mice exhibited faster tumor growth and lacked response to anti-PD-1 therapy, highlighting NO's essential role.
• NO donors inhibited melanoma cell proliferation and induced apoptosis in vitro.
• Anti-PD-1 therapy upregulated interferon pathway genes in wild-type but not iNOS knockout mice, with a specific NO-producing dendritic cell subset correlating with improved patient survival.

Conclusions:

• iNOS-derived NO is indispensable for effective anti-PD-1 immunotherapy in melanoma.
• NO promotes anti-tumor immunity by enhancing interferon signaling and immune cell activation.
• These findings reposition NO as a potential biomarker and therapeutic adjunct in melanoma treatment, contradicting its historically negative perception.