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Abstract：
A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine-specific demethylase 5D (KDM5D) copy number loss in SCC and explore its potential as a predictive biomarker for ataxia-telangiectasia and Rad3-related (ATR) inhibitor treatment. We evaluated KDM5D copy number loss in 173 surgically resected SCCs from male patients using fluorescence in situ hybridization. KDM5D copy number loss was detected in 75 of the 173 patients (43%). Genome-wide expression profiles of the transcription start sites (TSSs) were obtained from 17 SCCs, for which the cap analysis of gene expression assay was performed, revealing that upregulated genes in tumors with the KDM5D copy number loss are associated with \'cell cycle\', whereas downregulated genes in tumors with KDM5D copy number loss were associated with \'immune response\'. Clinicopathologically, SCCs with KDM5D copy number loss were associated with late pathological stage (p = 0.0085) and high stromal content (p = 0.0254). Multiplexed fluorescent immunohistochemistry showed that the number of tumor-infiltrating CD8+ /T-bet+ T cells was lower in SCCs with KDM5D copy number loss than in wild-type tumors. In conclusion, approximately 40% of the male patients with SCC exhibited KDM5D copy number loss. Tumors in patients who show this distinct phenotype can be \'cold tumors\', which are characterized by the paucity of tumor T-cell infiltration and usually do not respond to immunotherapy. Thus, they may be candidates for trials with ATR inhibitors.
摘要：
由于缺乏可靶向的驱动改变，有限数量的肺鳞状细胞癌（SCC）患者在临床上受益于分子靶向药物。我们旨在了解SCC中赖氨酸特异性脱甲基酶5D（KDM5D）拷贝数丢失的患病率和临床意义，并探讨其作为共济失调毛细血管扩张症和Rad3相关（ATR）抑制剂治疗的预测性生物标志物的潜力。我们使用荧光原位杂交评估了173例男性患者手术切除的SCC中的KDM5D拷贝数损失。在173名患者中的75名(43%)中检测到KDM5D拷贝数丢失。转录起始位点（TSS）的全基因组表达谱来自17个SCC，进行了基因表达测定的cap分析，揭示了在具有KDM5D拷贝数丢失的肿瘤中上调的基因与“细胞周期”有关，而在KDM5D拷贝数丢失的肿瘤中下调的基因与“免疫反应”相关。临床病理,具有KDM5D拷贝数丢失的SCCs与晚期病理阶段(p=0.0085)和高基质含量(p=0.0254)相关。多重荧光免疫组织化学显示，具有KDM5D拷贝数丢失的SCC中肿瘤浸润性CD8/T-betT细胞的数量低于野生型肿瘤。总之,约40%的男性SCC患者出现KDM5D拷贝数丢失.显示这种独特表型的患者的肿瘤可以是“冷肿瘤”，其特征是缺乏肿瘤T细胞浸润，通常对免疫疗法没有反应。因此，他们可能是ATR抑制剂试验的候选人.
