Department of Radiation Oncology, The First Hospital of China Medical University, Shenyang, China.
Department of Urology, The First Hospital of China Medical University, Shenyang, China.
Radiother Oncol. 2021 Jun;159:126-135. doi: 10.1016/j.radonc.2021.03.017. Epub 2021 Mar 26.
Radioresistance is a major barrier to the successful treatment of head and neck squamous cell carcinoma (HNSCC).
We took advantage of different types of data, including single-cell sequencing data, bulk tissue sequencing data and deconvolution data, to conduct a comprehensive analysis of HNSCC radiosensitivity at the cellular, patient, and cell type levels. Single-cell transcriptomes for 1388 primary cancer cells from a previous study were analysed. The TCGA HNSCC dataset including 499 primary HNSCC samples with RNA-seq data, DNA methylation data and clinical information were used for bulk tissue sequencing analyses and deconvolution.
We found that radiosensitivity clustering of HNSCC cells was highly consistent with molecular typing, where cancer cells of the atypical subtype exhibited a higher sensitivity than those of the classical and basal subtypes. The common radioresistant gene modules of the classical and basal subtypes were mainly associated with cell division and cell cycle regulation; the classical subtype specific radioresistant module was mainly associated with metabolic pathways; and the basal radioresistant subtype specific modules included two epithelial differentiation-related modules and a module mainly associated with endoplasmic reticulum, apoptosis and focal adhesion. We developed a radioresistance score using genes that affect both the cancer cell response to radiation and the patient response to radiotherapy. An enhanced cancer-immune interaction through the PD1-PDL1/PDL2 and TIM3-Galectin9 pathways was observed in radioresistant tumours, with foldchange = 2.88 (PD1), 1.44 (PDL1), 3.22 (PDL2), 1.47 (TIM3), 1.88 (Galectin9) respectively and FDR < 0.001. Transcriptional activities related to the hypoxia response, p53 pathway, NF-kappa-B pathway and inflammatory response were abnormally activated in the radioresistant tumours (FDR < 0.05).
This study comprehensively discussed the radioresistance of HNSCC, identified a group of HNSCCs that were likely to benefit from combined radiotherapy and immune checkpoint blockade, and proposed new targets for the treatment of radioresistant HNSCC.
放射抵抗是头颈部鳞状细胞癌（HNSCC）成功治疗的主要障碍。
我们利用包括单细胞测序数据、批量组织测序数据和去卷积数据在内的不同类型的数据，在细胞、患者和细胞类型水平上对 HNSCC 的放射敏感性进行了全面分析。分析了先前研究中 1388 个原发癌细胞的单细胞转录组。使用 TCGA HNSCC 数据集，该数据集包括 499 个具有 RNA-seq 数据、DNA 甲基化数据和临床信息的原发性 HNSCC 样本，进行批量组织测序分析和去卷积。
我们发现 HNSCC 细胞的放射敏感性聚类与分子分型高度一致，其中非典型亚型的癌细胞比经典型和基底型更敏感。经典型和基底型的常见放射抵抗基因模块主要与细胞分裂和细胞周期调节有关；经典型特异的放射抵抗模块主要与代谢途径有关；基底型特异的放射抵抗模块包括两个上皮分化相关模块和一个主要与内质网、细胞凋亡和焦点黏附有关的模块。我们使用影响癌细胞对辐射的反应和患者对放疗的反应的基因开发了一个放射抵抗评分。在放射抵抗肿瘤中观察到通过 PD1-PDL1/PDL2 和 TIM3-Galectin9 途径增强的癌症-免疫相互作用， foldchange = 2.88（PD1），1.44（PDL1），3.22（PDL2），1.47（TIM3），1.88（Galectin9）， FDR < 0.001。在放射抵抗肿瘤中，与缺氧反应、p53 途径、NF-kappa-B 途径和炎症反应相关的转录活性异常激活（FDR < 0.05）。
本研究全面探讨了 HNSCC 的放射抵抗性，确定了一组可能受益于联合放疗和免疫检查点阻断的 HNSCC，并为治疗放射抵抗性 HNSCC 提出了新的靶点。
