PD-L1+ neutrophils as novel biomarkers for stage IV melanoma patients treated with nivolumab

Abstract

Melanoma displays a rising incidence, and the mortality associated with metastatic form remains high. Monoclonal antibodies that block programmed death (PD-1) and PD Ligand 1 (PD-L1) network have revolutionized the history of metastatic disease. PD-L1 is expressed on several immune cells and can be also expressed on human neutrophils (PMNs). The role of peripheral blood PMNs as predictive biomarkers in anti-PD-1 therapy of melanoma is largely unknown. In this study, we aimed to determine activation status and PD-L1 expression on human neutrophils as possible novel biomarkers in stage IV melanoma patients (MPs). We found that PMNs from MPs displayed an activated phenotype and increased PD-L1 levels compared to healthy controls (HCs). Patients with lower PD-L1+ PMN frequencies displayed better progression-free survival (PFS) and overall survival (OS) compared to patients with high PD-L1+ PMN frequencies. Multivariate analysis showed that PD-L1+ PMNs predicted patient outcome in BRAF wild type MP subgroup but not in BRAF mutated MPs. PD-L1+ PMN frequency emerges as a novel biomarker in stage IV BRAF wild type MPs undergoing anti-PD-1 immunotherapy. Our findings suggest further evaluation of the role of neutrophil subsets and their mediators in melanoma patients undergoing immunotherapy.

Melanoma-derived soluble mediators modulate neutrophil biological properties and the release of neutrophil extracellular traps

“…In humans, the circulating neutrophil-to-lymphocyte ratio (NLR) has been used as a prognostic biomarker for melanoma [ 35 , 36 ], although these findings have some limitations due to PMN heterogeneity [ 37 ]. We demonstrated that peripheral blood PD-L1 + PMN frequency predicts patient prognosis and response to the anti-PD-1 agent nivolumab in patients with stage IV BRAF wild-type melanoma [ 11 ]. To go deeper inside the mechanisms linking melanoma cells and PMNs, we investigated the cross talk between melanoma cell lines and human PMNs purified from peripheral blood of healthy donors.…”

“…PD-L1 is also expressed on neutrophils and is associated with several diseases [ 8 – 10 ]. We recently demonstrated that peripheral blood PD-L1 + PMN frequency predicts patient prognosis and response to the anti-PD-1 agent nivolumab in patients with stage IV BRAF wild-type melanoma [ 11 ].…”

The double‐edged role of neutrophil heterogeneity in inflammatory diseases and cancers

“…Six phenotypically distinct human blood neutrophil populations were identified. The proportion and function of neutrophil subsets were shown to be correlated with melanoma stage, and their changes would favor the differentiation of different melanoma stages 353,354 . The profound study of neutrophils has also given hope for the treatment of melanoma.…”

“…The proportion and function of neutrophil subsets were shown to be correlated with melanoma stage, and their changes would favor the differentiation of different melanoma stages. 353 , 354 The profound study of neutrophils has also given hope for the treatment of melanoma. A recent study showed that neutrophils, especially TAN1, were isolated from mice underwent innate immune training by exposure to β‐glucan hold a stronger antitumor effect.…”

Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies

“…In cancer patients receiving anti-PD-1/PD-L1 therapy, a high neutrophil-to-lymphocyte ratio (NLR) is thought to have prognostic and predictive value [ 286 , 287 , 288 , 289 , 290 , 291 ]. Furthermore, neutrophils expressing PD-L1 were linked to a poor prognosis in patients with advanced melanoma and are thought to be a novel biomarker in stage IV melanoma patients receiving anti-PD-1 immunotherapy [ 292 ]. In addition, in melanoma patients, a high NLR value was associated with anti-PD-1/PD-L1 treatment failure [ 293 ].…”