肿瘤诱导的外周免疫抑制促进非小细胞肺癌患者的脑转移。
Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer.
机构信息
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
出版信息
Cancer Immunol Immunother. 2019 Sep;68(9):1501-1513. doi: 10.1007/s00262-019-02384-y. Epub 2019 Sep 5.
INTRODUCTION
Brain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis.
METHODS
Peripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation.
RESULTS
Patients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression.
CONCLUSIONS
The frequency of PD-L1 myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1 myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.
简介
脑转移是肺癌患者发病率和死亡率的重要来源。肺癌可导致局部和全身免疫抑制，促进肿瘤生长和扩散。免疫抑制的一种机制是肿瘤诱导表达程序性死亡配体 1（PD-L1）的髓样细胞扩张。在这里，我们研究了有或没有脑转移的 NSCLC 患者的外周血免疫表型。
方法
从患有肺癌脑转移瘤和肺转移前癌症的患者中采集外周血。通过流式细胞术定量抑制性单核细胞、髓系来源的抑制性细胞（MDSCs）和调节性 T 细胞（Tregs）。通过 ELISpot 分析 T 细胞反应性。从肿瘤衍生细胞培养物中收集脑转移条件培养基，并通过 ELISA 分析细胞因子。用脑转移条件培养基刺激幼稚单核细胞，以评估 PD-L1 刺激。
结果
与早期肺转移前患者和健康对照组相比，患有脑转移性肺癌的患者外周血单核细胞 PD-L1、MDSC 丰度和 Treg 百分比增加。外周血单核细胞 PD-L1 升高的患者反应性 T 细胞较少，生存情况较差。脑转移条件培养基刺激增加单核细胞 PD-L1，且条件培养基中 IL-6 水平与 PD-L1 诱导相关。用抗 IL-6 或抗 IL-6 受体抗体治疗可降低 PD-L1 表达。总之，患有肺癌和脑转移的患者表现出多种外周免疫抑制标志物。
结论
PD-L1 髓样细胞的频率与脑转移的存在相关。肿瘤衍生的 IL-6 能够在体外诱导 PD-L1 髓样细胞，表明在外周血中监测免疫抑制因子可能有助于识别某些患者的新治疗靶点。
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