Arasanz Hugo, Bocanegra Ana Isabel, Morilla Idoia, Fernández-Irigoyen Joaquín, Martínez-Aguillo Maite, Teijeira Lucía, Garnica Maider, Blanco Ester, Chocarro Luisa, Ausin Karina, Zuazo Miren, Fernández-Hinojal Gonzalo, Echaide Miriam, Fernández-Rubio Leticia, Piñeiro-Hermida Sergio, Ramos Pablo, Mezquita Laura, Escors David, Vera Ruth, Kochan Grazyna
Oncoimmunology Group, Navarrabiomed, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea St., 3, 31008 Pamplona, Spain.
Medical Oncology Department, Hospital Universitario de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
Cancers (Basel). 2022 Aug 9;14(16):3846. doi: 10.3390/cancers14163846.
Single-agent immunotherapy has been widely accepted as frontline treatment for advanced non-small cell lung cancer (NSCLC) with high tumor PD-L1 expression, but most patients do not respond and the mechanisms of resistance are not well known. Several works have highlighted the immunosuppressive activities of myeloid subpopulations, including low-density neutrophils (LDNs), although the context in which these cells play their role is not well defined. We prospectively monitored LDNs in peripheral blood from patients with NSCLC treated with anti-PD-1 immune checkpoint inhibitors (ICIs) as frontline therapy, in a cohort of patients treated with anti-PD1 immunotherapy combined with chemotherapy (CT+IT), and correlated values with outcomes. We explored the underlying mechanisms through ex vivo experiments. Elevated baseline LDNs predict primary resistance to ICI monotherapy in patients with NSCLC, and are not associated with response to CT+IT. Circulating LDNs mediate resistance in NSCLC receiving ICI as frontline therapy through humoral immunosuppression. A depletion of this population with CT+IT might overcome resistance, suggesting that patients with high PD-L1 tumor expression and high baseline LDNs might benefit from this combination. The activation of the HGF/c-MET pathway in patients with elevated LDNs revealed by quantitative proteomics supports potential drug combinations targeting this pathway.
单药免疫疗法已被广泛接受为晚期非小细胞肺癌（NSCLC）伴高肿瘤程序性死亡配体1（PD-L1）表达的一线治疗方法，但大多数患者无反应，且耐药机制尚不清楚。多项研究强调了髓系亚群的免疫抑制活性，包括低密度中性粒细胞（LDN），尽管这些细胞发挥作用的背景尚不清楚。我们前瞻性地监测了接受抗程序性死亡蛋白1（PD-1）免疫检查点抑制剂（ICI）作为一线治疗的NSCLC患者外周血中的LDN，以及一组接受抗PD-1免疫疗法联合化疗（CT+IT）的患者，并将相关值与预后进行关联。我们通过体外实验探索了潜在机制。基线LDN升高预示NSCLC患者对ICI单药治疗的原发性耐药，且与对CT+IT的反应无关。循环LDN通过体液免疫抑制介导接受ICI作为一线治疗的NSCLC的耐药。CT+IT使该群体减少可能克服耐药，这表明高PD-L1肿瘤表达和高基线LDN的患者可能从这种联合治疗中获益。定量蛋白质组学揭示的LDN升高患者中肝细胞生长因子（HGF）/c-甲硫氨酸（c-MET）通路的激活支持了针对该通路的潜在药物联合使用。
