Core Unit Bioinformatics, Berlin Institute of Health (BIH), Berlin, Germany.
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Int J Cancer. 2020 Oct 15;147(8):2293-2302. doi: 10.1002/ijc.33123. Epub 2020 Jun 18.
Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date. We analyzed viral status, gene expression signatures, mutational load and mutational signatures in whole exome and RNA-sequencing data of the HNSCC TCGA dataset (n = 496) and a validation set (DKTK MASTER cohort, n = 10). Public single-cell gene expression data from 17 HPV-negative HNSCC were separately reanalyzed. APOBEC3-associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. This association was restricted to HPV-negative HNSCC samples. An APOBEC-enriched, HPV-negative subgroup was identified, that showed higher T-cell inflammation and immune checkpoint expression, as well as expression of APOBEC3 genes. Mutations in immune-evasion pathways were also enriched in these tumors. Analysis of single-cell sequencing data identified expression of APOBEC3B and 3C genes in malignant cells. We identified an APOBEC-enriched subgroup of HPV-negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy.
免疫检查点抑制导致部分头颈部鳞状细胞癌 (HNSCC) 患者产生应答。但目前缺乏强大的生物标志物。我们分析了 HNSCC TCGA 数据集（n=496）和验证集（DKTK MASTER 队列，n=10）的全外显子组和 RNA 测序数据中的病毒状态、基因表达特征、突变负荷和突变特征。还分别重新分析了来自 17 例 HPV 阴性 HNSCC 的公共单细胞基因表达数据。APOBEC3 相关的 TCW 基序突变，而不是总单核苷酸变异负担，与炎症显著相关。这种关联仅限于 HPV 阴性 HNSCC 样本。鉴定出一个 APOBEC 富集、HPV 阴性亚组，其表现出更高的 T 细胞炎症和免疫检查点表达，以及 APOBEC3 基因的表达。这些肿瘤中还富集了免疫逃逸途径的突变。单细胞测序数据的分析鉴定出恶性细胞中 APOBEC3B 和 3C 基因的表达。我们鉴定出一个 APOBEC 富集的 HPV 阴性 HNSCC 亚组，具有独特的免疫原性表型，可能介导对免疫治疗的反应。
