Peripheral Blood Neutrophils and Monocytes Predict Disease Progression in Stage III Melanoma Patients Treated With Anti Programmed Cell Death Protein‐1 (PD‐1) Inhibitors

Melanoma is a global health issue, with an increasing incidence in recent years. Immune checkpoint inhibitors (ICIs, e.g., antiprogrammed cell death protein 1 [PD-1]) and targeted therapies (e.g., BRAF/MEK inhibitors) have revolutionized treatment for melanoma patients (MPs), but prognostic markers of drug response and disease progression remain elusive. We conducted a prospective baseline and follow-up study to investigate peripheral blood neutrophils and monocytes as immune biomarkers in stage III MPs receiving either anti-PD-1 therapy or B-type rapidly accelerated fibrosarcoma (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibitors. Sixty-four stage III MPs were prospectively recruited, of whom 42 received anti-PD-1 therapy, and 22 received BRAF/MEK inhibitors. Neutrophils and monocytes were isolated and analyzed by flow cytometry, while plasma concentrations of neutrophil-related mediators and neutrophil extracellular trap (NET) biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). In MPs, neutrophils displayed an activated phenotype (CD16⁺ CD62L^-), and both neutrophils and monocytes had higher PD-1 ligand (PD-L1) expression, compared with healthy controls (HCs). Importantly, higher percentages of CD16⁺ CD62L^- and PD-L1⁺ neutrophils and PD-L1⁺ monocytes-but not higher levels of neutrophil-related mediators and NET biomarkers-were associated with disease progression only in MPs treated with anti-PD-1 therapy but not in those treated with BRAF/MEK inhibitors. This study reveals that a specific neutrophil and monocyte phenotype can predict clinical responses exclusively in ICI-treated patients, highlighting their potential as prognostic biomarkers before starting the immune checkpoint inhibition in melanoma.