Berghmans Eline, Jacobs Julie, Deben Christophe, Hermans Christophe, Broeckx Glenn, Smits Evelien, Maes Evelyne, Raskin Jo, Pauwels Patrick, Baggerman Geert
Centre for Proteomics, University of Antwerp, 2020 Antwerpen, Belgium.
Health Unit, VITO, 2400 Mol, Belgium.
Cancers (Basel). 2020 Apr 2;12(4):863. doi: 10.3390/cancers12040863.
(1) Background: Therapeutic blocking of the interaction between programmed death-1 (PD-1) with its ligand PD-L1, an immune checkpoint, is a promising approach to restore the antitumor immune response. Improved clinical outcomes have been shown in different human cancers, including non-small cell lung cancer (NSCLC). Unfortunately, still a high number of NSCLC patients are treated with immunotherapy without obtaining any clinical benefit, due to the limitations of PD-L1 protein expression as the currently sole predictive biomarker for clinical use; (2) Methods: In this study, we applied mass spectrometry imaging (MSI) to discover new protein biomarkers, and to assess the possible correlation between candidate biomarkers and a positive immunotherapy response by matrix-assisted laser desorption/ionization (MALDI) MSI in 25 formalin-fixed paraffin-embedded (FFPE) pretreatment tumor biopsies (Biobank@UZA); (3) Results: Using MALDI MSI, we revealed that the addition of neutrophil defensin 1, 2 and 3 as pretreatment biomarkers may more accurately predict the outcome of immunotherapy treatment in NSCLC. These results were verified and confirmed with immunohistochemical analyses. In addition, we provide in-vitro evidence of the immune stimulatory effect of neutrophil defensins towards cancer cells; and (4) Conclusions: With proteomic approaches, we have discovered neutrophil defensins as additional prospective biomarkers for an anti-PD-(L)1 immunotherapy response. Thereby, we also demonstrated that the neutrophil defensins contribute in the activation of the immune response towards cancer cells, which could provide a new lead towards an anticancer therapy.
(1) 背景：程序性死亡受体1（PD-1）与其配体程序性死亡配体1（PD-L1）相互作用的治疗性阻断是一种恢复抗肿瘤免疫反应的有前景的方法。在包括非小细胞肺癌（NSCLC）在内的不同人类癌症中已显示出改善的临床结果。不幸的是，由于PD-L1蛋白表达作为目前唯一用于临床的预测生物标志物存在局限性，仍有大量NSCLC患者接受免疫治疗却未获得任何临床益处；(2) 方法：在本研究中，我们应用质谱成像（MSI）来发现新的蛋白质生物标志物，并通过基质辅助激光解吸电离（MALDI）MSI评估25份福尔马林固定石蜡包埋（FFPE）预处理肿瘤活检样本（UZA生物样本库）中候选生物标志物与免疫治疗阳性反应之间的可能相关性；(3) 结果：使用MALDI MSI，我们发现添加中性粒细胞防御素1、2和3作为预处理生物标志物可能更准确地预测NSCLC免疫治疗的结果。这些结果通过免疫组织化学分析得到验证和确认。此外，我们提供了中性粒细胞防御素对癌细胞免疫刺激作用的体外证据；(4) 结论：通过蛋白质组学方法，我们发现中性粒细胞防御素是抗PD-(L)1免疫治疗反应的额外潜在生物标志物。因此，我们还证明了中性粒细胞防御素有助于激活针对癌细胞的免疫反应，这可能为抗癌治疗提供新的线索。
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