Background

Monoclonal antibodies (ICI) targeting the immune checkpoint PD-1/PD-L1 alone or in combination with chemotherapy have demonstrated relevant benefits and established new standards of care in first-line treatment for advanced non-oncogene addicted non-small cell lung cancer (NSCLC).

However, a relevant percentage of NSCLC patients, even with high PD-L1 expression, did not respond to ICI, highlighting the presence of intracellular resistance mechanisms that could be dependent on high PD-L1 levels. The intracellular signaling induced by PD-L1 in tumor cells and their correlation with angiogenic signaling pathways are not yet fully elucidated.

Methods

The intrinsic role of PD-L1 was initially checked in two PD-L1 overexpressing NSCLC cells by transcriptome profile and kinase array. The correlation of PD-L1 with VEGF, PECAM-1, and angiogenesis was evaluated in a cohort of advanced NSCLC patients. The secreted cytokines involved in tumor angiogenesis were assessed by Luminex assay and their effect on Huvec migration by a non-contact co-culture system.

Results

PD-L1 overexpressing cells modulated pathways involved in tumor inflammation and JAK-STAT signaling. In NSCLC patients, PD-L1 expression was correlated with high tumor intra-vasculature. When challenged with PBMC, PD-L1 overexpressing cells produced higher levels of pro-angiogenic factors compared to parental cells, as a consequence of STAT signaling activation. This increased production of cytokines involved in tumor angiogenesis largely stimulated Huvec migration. Finally, the addition of the anti-antiangiogenic agent nintedanib significantly reduced the spread of Huvec cells when exposed to high levels of pro-angiogenic factors.

Conclusions

In this study, we reported that high PD-L1 modulates STAT signaling in the presence of PBMC and induces pro-angiogenic factor secretion. This could enforce the role of PD-L1 as a crucial regulator of the tumor microenvironment stimulating tumor progression, both as an inhibitor of T-cell activity and as a promoter of tumor angiogenesis.

中文翻译：

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PD-L1 过表达诱导 STAT 信号传导并促进非小细胞肺癌 (NSCLC) 中促血管生成细胞因子的分泌

 背景

单独针对免疫检查点 PD-1/PD-L1 或与化疗联合使用的单克隆抗体 (ICI) 已显示出相关益处，并为晚期非癌基因成瘾性非小细胞肺癌的一线治疗建立了新的护理标准。非小细胞肺癌）。

然而，相当比例的 NSCLC 患者，即使 PD-L1 表达较高，也对 ICI 没有反应，这凸显了可能依赖于高 PD-L1 水平的细胞内耐药机制的存在。肿瘤细胞中 PD-L1 诱导的细胞内信号传导及其与血管生成信号通路的相关性尚未完全阐明。

 方法

最初通过转录组谱和激酶阵列在两种 PD-L1 过表达 NSCLC 细胞中检查 PD-L1 的内在作用。在一组晚期 NSCLC 患者中评估了 PD-L1 与 VEGF、PECAM-1 和血管生成的相关性。通过 Luminex 测定评估参与肿瘤血管生成的分泌细胞因子，并通过非接触共培养系统评估它们对 Huvec 迁移的影响。

 结果

PD-L1 过表达细胞调节参与肿瘤炎症和 JAK-STAT 信号传导的通路。在 NSCLC 患者中，PD-L1 表达与肿瘤血管内的高水平相关。当受到 PBMC 攻击时，由于 STAT 信号传导激活，PD-L1 过表达细胞与亲代细胞相比产生了更高水平的促血管生成因子。参与肿瘤血管生成的细胞因子的产生在很大程度上刺激了 Huvec 迁移。最后，当暴露于高水平的促血管生成因子时，添加抗血管生成剂尼达尼布显着减少了 Huvec 细胞的扩散。

 结论

在这项研究中，我们报道了高 PD-L1 在 PBMC 存在的情况下调节 STAT 信号传导并诱导促血管生成因子分泌。这可以强化 PD-L1 作为刺激肿瘤进展的肿瘤微环境的关键调节剂的作用，既作为 T 细胞活性的抑制剂，又作为肿瘤血管生成的促进剂。