PDF(Pubmed)
Abstract：
Adenoid cystic carcinoma (AdCC) is a slow-growing salivary gland malignancy that relapses frequently. AdCCs of the submandibular gland exhibit unique differences in prognosis and treatment response to adjuvant radiotherapy compared to other sites, yet the role of tumor anatomic subsite on gene expression and tumor immune microenvironment (TIME) composition remains unclear. We used 87 samples, including 48 samples (27 AdCC and 21 normal salivary gland tissue samples) from 4 publicly available AdCC RNA sequencing datasets, a validation set of 33 minor gland AdCCs, and 39 samples from an in-house cohort (30 AdCC and 9 normal salivary gland samples). RNA sequencing data were used for single sample gene set enrichment analysis and TIME deconvolution. Quantitative PCR and multiplex immunofluorescence were performed on the in-house cohort. Wilcoxon rank-sum, nonparametric equality-of-medians tests and linear regression models were used to evaluate tumor subsite differences. AdCCs of different anatomic subsites including parotid, submandibular, sublingual, and minor salivary glands differed with respect to expression of several key tumorigenic pathways. Among the three major salivary glands, the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway signature was significantly underexpressed in AdCC of submandibular compared to parotid and sublingual glands while this association was not observed among normal glands. Additionally, the NRF2 pathway, whose expression was associated with favorable overall survival, was overexpressed in AdCCs of parotid gland compared to minor and submandibular glands. The TIME deconvolution identified differences in CD4+ T cell populations between AdCC of major and minor glands and natural killer (NK) cells among AdCC of minor, submandibular, and parotid glands while plasma cells were enriched in normal submandibular glands compared to other normal gland controls. Our data reveal key molecular differences in AdCC of different anatomic subsites. The ROS and NRF2 pathways are underexpressed in submandibular and minor AdCCs compared to parotid gland AdCCs, and NRF2 pathway expression is associated with favorable overall survival. The CD4+ T, NK, and plasma cell populations also vary by tumor subsites, suggesting that the observed submandibular AdCC tumor-intrinsic pathway differences may be responsible for influencing the TIME composition and survival differences.
摘要：
腺样囊性癌（AdCC）是一种生长缓慢的唾液腺恶性肿瘤，经常复发。与其他部位相比，颌下腺的AdCC在预后和对辅助放疗的治疗反应方面表现出独特的差异，然而，肿瘤解剖亚位点对基因表达和肿瘤免疫微环境（TIME）组成的作用仍不清楚。我们用了87个样本,包括来自4个公开的AdCCRNA测序数据集的48个样本（27个AdCC和21个正常唾液腺组织样本），33个次要腺体AdCC的验证集，和39个来自内部队列的样本（30个AdCC和9个正常唾液腺样本）。RNA测序数据用于单样品基因集富集分析和TIME去卷积。对内部队列进行定量PCR和多重免疫荧光。威尔科克森等级和，非参数中位数相等检验和线性回归模型用于评估肿瘤亚位点差异.包括腮腺在内的不同解剖亚位点的AdCC，颌下,舌下，和小唾液腺在几个关键致瘤途径的表达方面存在差异。在三大唾液腺中，与腮腺和舌下腺相比,下颌下腺AdCC中的活性氧(ROS)/核因子类2相关因子(NRF2)通路特征显著表达不足,而在正常腺体中未观察到这种关联.此外,NRF2途径，其表达与良好的总生存率相关，与小腺和下颌下腺相比，腮腺的AdCC中过表达。TIME反卷积确定了主要和次要腺体的AdCC与次要AdCC中的自然杀伤（NK）细胞之间的CD4T细胞种群差异，颌下,与其他正常腺体对照相比，正常颌下腺中的浆细胞富集和腮腺。我们的数据揭示了不同解剖亚位点的AdCC的关键分子差异。与腮腺AdCC相比，ROS和NRF2途径在颌下和次要AdCC中表达不足，和NRF2途径表达与有利的总生存期相关。CD4+T,NK,浆细胞群也因肿瘤亚位点而异，这表明所观察到的颌下AdCC肿瘤内在途径差异可能是影响TIME组成和生存差异的原因。
