The identification of biomarkers related to treatment in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) represents a significant challenge. The aim of this study was to determine the predictive value of macrophage-related markers assessed in plasma and tissue samples of patients with NSCLC undergoing ICI treatment. This bicentric study included a prospective cohort of 88 patients with advanced NSCLC who received first-line therapy with ICI (either as monotherapy or in combination with chemotherapy) or chemotherapy alone (CT). Samples were collected from the patients at baseline and during follow-up. Plasma levels of CSF-1 and IL-34 were measured using ELISA, while expression levels of the macrophage receptors CD163 and CSF-1-R were evaluated using immunohistochemistry on lung biopsies. At baseline, the median plasma CSF-1 expression was higher in patients who did not respond to immunotherapy compared to those who responded (8898 pg/mL vs. 14031 pg/mL, p = 0.0005). Importantly, high CSF-1 levels at the initial assessment were associated with disease progression regardless of the treatment received. Furthermore, high CSF-1 levels were associated with shorter progression-free survival (PFS) and overall survival (OS) in patients receiving ICI therapy, but not in those treated with chemotherapy. There was no correlation between IL-34, CSF-1R, CD163 and therapeutic response. We observed in vitro that the activation of lymphocytes mediated by pembrolizumab was hindered by the treatment of PBMC with recombinant CSF-1, suggesting that CSF-1 creates a systemic immunosuppressive state that interferes with ICI treatment. In conclusion, baseline CSF-1 levels represent a potential predictive marker to ICI treatment in NSCLC.

识别与接受免疫检查点抑制剂（ICIs）治疗的非小细胞肺癌（NSCLC）患者的治疗相关的生物标志物是一项重大挑战。本研究的目的是确定接受 ICI 治疗的 NSCLC 患者血浆和组织样本中评估的巨噬细胞相关标记物的预测价值。这项双中心研究包括 88 名晚期 NSCLC 患者的前瞻性队列，他们接受 ICI 一线治疗（作为单一疗法或与化疗联合）或单独化疗 (CT)。在基线和随访期间从患者身上收集样本。使用 ELISA 测量 CSF-1 和 IL-34 的血浆水平，同时使用肺活检的免疫组织化学评估巨噬细胞受体 CD163 和 CSF-1-R 的表达水平。基线时，与免疫治疗有反应的患者相比，对免疫治疗无反应的患者的中位血浆 CSF-1 表达较高（8898 pg/mL vs. 14031 pg/mL，p = 0.0005）。重要的是，无论接受何种治疗，初始评估时的高 CSF-1 水平都与疾病进展相关。此外，在接受 ICI 治疗的患者中，高 CSF-1 水平与较短的无进展生存期 (PFS) 和总生存期 (OS) 相关，但与接受化疗的患者无关。IL-34、CSF-1R、CD163 与治疗反应之间不存在相关性。我们在体外观察到，重组 CSF-1 治疗 PBMC 阻碍了派姆单抗介导的淋巴细胞活化，表明 CSF-1 产生了干扰 ICI 治疗的全身免疫抑制状态。总之，基线 CSF-1 水平代表了 NSCLC ICI 治疗的潜在预测标志物。