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.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-003420.
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.
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.
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).
Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC.
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。
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。
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）。
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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