在晚期和转移性头颈部鳞状细胞癌患者中，对抗 PD-1 免疫检查点抑制剂有反应者与无反应者的 DNA 甲基化谱不同。
DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma.
机构信息
Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.
Department of Medicine I, Christian Doppler Laboratory for Personalized Immunotherapy, Medical University of Vienna, Vienna, Austria.
出版信息
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-003420.
BACKGROUND
Biomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory parameters and DNA methylation profiling in patients with HNSCC treated with anti-PD-1 ICI.
METHODS
We identified patients with HNSCC that were treated with anti-PD-1 ICI therapy in the recurrent or metastatic setting after progression to platinum-based chemotherapy in two independent centers. We analyzed DNA methylation profiles of >850.000 CpG sites in tumor specimens of these patients by Infinium MethylationEPIC microarrays, immune cell density in the tumor microenvironment (CD8, CD3, CD45RO, forkhead box P3 (FOXP3), CD68), PD-1 and programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry, and blood inflammation markers (platelet-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio). DNA methylation profiles and immunological markers were bioinformatically and statistically correlated with radiological response to anti-PD-1 ICI.
RESULTS
37 patients with HNSCC (median age of 62 years; range 49-83; 8 (21.6%) women, 29 (78.4%) men) were included (Center 1 N=26, 70.3%; Center 2 N=11, 29.7%). Median number of prior systemic therapies was 1 (range 1-4). Five out of 37 (13.5%) patients achieved an objective response to ICI. Median progression-free survival and median overall survival times were 3.7 months (range 0-22.9) and 9.0 months (range 0-38.8), respectively. Microarray analyses revealed a methylation signature including both hypomethylation and hypermethylation which was predictive for response to ICI and included several genes involved in cancer-related molecular pathways. Over-represented differentially methylated genes between responders and non-responders were associated with 'Axon guidance', 'Hippo signaling', 'Pathways in cancer' and 'MAPK signaling'. A statistically significant correlation of PD-L1 expression and response was present (p=0.0498).
CONCLUSIONS
Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC.
背景
对头颈鳞状细胞癌（HNSCC）患者进行抗程序性细胞死亡 1（PD-1）免疫检查点抑制剂（ICI）治疗的反应预测生物标志物对于个性化治疗方法非常重要。我们研究了在接受抗 PD-1 ICI 治疗的 HNSCC 患者中炎症参数和 DNA 甲基化谱的预测潜力。
方法
我们在两个独立的中心中确定了在铂类化疗进展后接受抗 PD-1 ICI 治疗的复发或转移性 HNSCC 患者。我们通过 Infinium MethylationEPIC 微阵列分析了这些患者肿瘤标本中 >850,000 个 CpG 位点的 DNA 甲基化谱，分析了肿瘤微环境中的免疫细胞密度（CD8、CD3、CD45RO、叉头框 P3（FOXP3）、CD68）、PD-1 和程序性细胞死亡配体 1（PD-L1）的免疫组织化学表达，以及血液炎症标志物（血小板与淋巴细胞比、白细胞与淋巴细胞比、单核细胞与淋巴细胞比、中性粒细胞与淋巴细胞比）。通过生物信息学和统计学方法将 DNA 甲基化谱和免疫标志物与抗 PD-1 ICI 的影像学反应相关联。
结果
37 例 HNSCC 患者（中位年龄 62 岁；范围 49-83；8 例（21.6%）女性，29 例（78.4%）男性）入组（中心 1 26 例，70.3%；中心 2 11 例，29.7%）。中位治疗线数为 1（范围 1-4）。37 例患者中有 5 例（13.5%）对 ICI 有客观反应。中位无进展生存期和总生存期分别为 3.7 个月（范围 0-22.9）和 9.0 个月（范围 0-38.8）。微阵列分析显示，一种包括低甲基化和高甲基化的甲基化特征可预测 ICI 的反应，其中包括几个参与癌症相关分子途径的基因。 responder 和 non-responder 之间差异甲基化基因的过度表达与“轴突导向”、“Hippo 信号”、“癌症途径”和“MAPK 信号”有关。PD-L1 表达与反应之间存在统计学显著相关性（p=0.0498）。
结论
我们的研究结果表明，肿瘤 DNA 甲基化谱可能有助于预测 HNSCC 患者对 ICI 的反应。
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