Prognostic value of novel immune-related genomic biomarkers identified in head and neck squamous cell carcinoma
Prognostic value of novel immune-related genomic biomarkers identified in head and neck squamous cell carcinoma
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在头颈鳞状细胞癌中发现的新型免疫相关基因组生物标志物的预后价值
DOI：
10.1136/jitc-2019-000444
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Chen, Yun
中科院分区：
文献类型：
--
作者：
Yao, Yao;Yan, Zhongyi;Chen, Yun
肿瘤微环境中的免疫应答在肿瘤发生中起关键作用，并决定头颈部鳞状细胞癌（HNSCC）的临床结局。然而，迄今为止，已经鉴定出能够估计HNSCC患者预后的稳健、可靠的免疫相关生物标志物的缺乏。方法对5例HNSCC患者的肿瘤和匹配的癌旁组织进行高通量RNA测序，并评估从nCounter PanCancer免疫分析面板中选择的730种免疫相关转录物的免疫特征表达。在训练队列中进行生存分析，所述训练队列由从癌症基因组图谱（TCGA）数据库检索的416个HNSCC病例组成。使用弹性净惩罚考克斯回归和后向逐步考克斯回归分析建立预后标志。结果通过115例HNSCC患者的独立队列，使用组织微阵列和免疫组织化学染色进行验证。通过估计RNA转录物的相对子集的细胞类型鉴定（CIBERSORT）也用于估计22种免疫细胞类型的相对分数及其与预后生物标志物的相关系数。结果通过RNA测序，共发现248个免疫相关基因在配对的肿瘤组织和正常组织中差异表达。在训练TCGA队列中进行过程筛选后，四个免疫相关基因（PVR、TNFRSF 12 A、IL 21 R和SOCS 1）与总生存期（OS）显着相关。将这些基因与Path_N分期相结合，建立了一个多重模型，该模型在确定5年OS方面具有更好的性能（受试者工作特征（ROC）分析，曲线下面积（AUC）=0.709）。在115例HNSCC患者中进行了进一步的基于蛋白质的验证。类似地，PVR和TNFRSF 12 A的高表达与较差的OS相关（Kaplan-Meier p=0.017和0.0032），而IL 21 R和SOCS 1的高表达表明有利的OS（Kaplan-Meier p<0.0001和=0.0018）。具有Path_N分期的整合模型在OS评估中仍然显示出有效性（Kaplan-Meier p<0.0001，ROC AUC=0.893）。此外，这4个预后基因与活化的CD 8 + T细胞、CD 4 + T细胞、滤泡辅助性T细胞和调节性T细胞显著相关，提示这些基因可能参与HNSCC的免疫调节和发生发展。结论包含免疫相关生物标志物和临床病理因素的成熟模型可能成为HNSCC预后预测的有前途的工具。
Background The immune response within the tumor microenvironment plays a key role in tumorigenesis and determines the clinical outcomes of head and neck squamous cell carcinoma (HNSCC). However, to date, a paucity of robust, reliable immune-related biomarkers has been identified that are capable of estimating prognosis in HNSCC patients. Methods High-throughput RNA sequencing was performed in tumors and matched adjacent tissues from five HNSCC patients, and the immune signatures expression of 730 immune-related transcripts selected from the nCounter PanCancer Immune Profiling Panel were assessed. Survival analyzes were performed in a training cohort, consisting of 416 HNSCC cases, retrieved from The Cancer Genome Atlas (TCGA) database. A prognostic signature was built, using elastic net-penalized Cox regression and backward, stepwise Cox regression analyzes. The outcomes were validated by an independent cohort of 115 HNSCC patients, using tissue microarrays and immunohistochemistry staining. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was also used to estimate the relative fractions of 22 immune-cell types and their correlations coefficients with prognostic biomarkers. Results Collectively, 248 immune-related genes were differentially expressed in paired tumors and normal tissues using RNA sequencing. After process screening in the training TCGA cohort, four immune-related genes (PVR, TNFRSF12A, IL21R, and SOCS1) were significantly associated with overall survival (OS). Integrating these genes with Path_N stage, a multiplex model was built and suggested better performance in determining 5 years OS (receiver operating characteristic (ROC) analysis, area under the curve (AUC)=0.709) than others. Further protein-based validation was conducted in 115 HNSCC patients. Similarly, high expression of PVR and TNFRSF12A were associated with poor OS (Kaplan-Meier p=0.017 and 0.0032), while high expression of IL21R and SOCS1 indicated favorable OS (Kaplan-Meier p<0.0001 and =0.0018). The integrated model with Path_N stage still demonstrated efficacy in OS evaluation (Kaplan-Meier p<0.0001, ROC AUC=0.893). Besides, the four prognostic genes were significantly correlated with activated CD8+ T cells, CD4+ T cells, follicular helper T cells and regulatory T cells, implying the possible involvement of these genes in the immunoregulation and development of HNSCC. Conclusions The well-established model encompassing both immune-related biomarkers and clinicopathological factor might serve as a promising tool for the prognostic prediction of HNSCC.