Establishment and validation of immune microenvironmental gene signatures for predicting prognosis in patients with head and neck squamous cell carcinoma.

Tumor cells influencing the microenvironment are essential for restrained immunity in head and neck squamous cell carcinoma (HNSCC). There has been considerable progress in the research on monoclonal antibodies for antigen-specific immunotherapy that overcome immunosuppressive checkpoint receptor/ligand signaling in patients with HNSCC. However, alteration of immunogenicity and formation of neoantigens that lead to dysregulation and immunosuppression in the HNSCC microenvironment is not well-defined. The aim of this study was to quantify the Immune, Stromal, and ESTIMATE scores based on the gene matrix of patients with HNSCC reported in The Cancer Genome Atlas (TCGA). We examined the association of the Immune, Stromal, and ESTIMATE scores with the pathologic characteristics of patients with HNSCC, using weighted gene co-expression network (WGCNA) and protein-protein interaction (PPI) analyses, and selected 17 hub gene signatures from the key gene module that was mostly correlated to immunocyte infiltration. Gene functional enrichment showed that this key gene module was closely related to the regulation of immune cell activation and its relevant pathways. In the prognostic analysis, high expression of CD3E, SASH3, CD2, SIRPG, UBASH3A, IKZF1, SPN, IL10RA, SLA, and CD3G was significantly associated with a good prognosis. Consequently, these prognosis-related genes were validated via analysis of mRNA expression in tumor-infiltrating lymphocytes (TILs) and matched peripheral blood lymphocytes (PBLs) in ten patients with HNSCC, and the expression of these genes was significantly higher in TILs compared to that in PBLs. These findings provide a novel understanding of the tumor immune targets for improved therapeutic regimes in patients with HNSCC.

Wang J ，Tian Y ，Zhu G ，Li Z ，Wu Z ，Wei G ，Zhuang L ，Li Z ，Chen X ，Zhang X ，Zheng J ，Cai G ... -  《-》

Tumor Mutation Burden, Immune Cell Infiltration, and Construction of Immune-Related Genes Prognostic Model in Head and Neck Cancer.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and the prognosis of HNSCC remains bleak. Numerous studies revealed that the tumor mutation burden (TMB) could predict the survival outcomes of a variety of tumors. Objectives: This study aimed to investigate the TMB and immune cell infiltration in these patients and construct an immune-related genes (IRGs) prognostic model. Methods: The expression data of 546 HNSCC patients were obtained from The Cancer Genome Atlas (TCGA) database. All patients were divided into high- and low- TMB groups, and the relationship between TMB and clinical relevance was further analyzed. The differentially expressed genes (DEGs) were identified using the R software package, limma. Functional enrichment analyses were conducted to identify the significantly enriched pathways between two groups. CIBERSORT algorithm was adopted to calculate the abundance of 22 leukocyte subtypes. The IRGs prognostic model was constructed via the multivariate Cox regression analysis. Results: Missense mutation and single nucleotide variants (SNV) were the most predominant mutation types in HNSCC. TP53, TTN, and FAT1 were the most frequently mutated genes. Patients with high TMB were observed with worse survival outcomes. The functional analysis of TMB associated DEGs showed that the identified DEGs mainly involved in spliceosome, RNA degradation, proteasome, and RNA polymerase pathways. We observed that macrophages, T cells CD8, and T cells CD4 memory were the most commonly infiltrated subtypes of immune cells in HNSCC. Finally, an IRGs prognostic model was constructed, and the AUC of the ROC curve was 0.635. Conclusions: Our results suggest that high TMB is associated with poor prognosis in HNSCC patients. The constructed model has potential prognostic value for the prognosis of these individuals, and it needs to be further validated in large-scale and prospective studies.

Jiang AM ，Ren MD ，Liu N ，Gao H ，Wang JJ ，Zheng XQ ，Fu X ，Liang X ，Ruan ZP ，Tian T ，Yao Y ... -  《International Journal of Medical Sciences》

Transcriptome analysis reveals the link between lncRNA-mRNA co-expression network and tumor immune microenvironment and overall survival in head and neck squamous cell carcinoma.

Zhong Z ，Hong M ，Chen X ，Xi Y ，Xu Y ，Kong D ，Deng J ，Li Y ，Hu R ，Sun C ，Liang J ... -  《BMC Medical Genomics》

Development and validation of a novel ferroptosis-related gene signature for predicting prognosis and immune microenvironment in head and neck squamous cell carcinoma.

Ferroptosis plays an important role across variable cancer types. However, few studies have focused on the prognostic patterns of ferroptosis-related genes in HNSCC. Cohorts with mRNA expression profiles, as well as corresponding clinical data of HNSCC patients from published studies, were collected and consolidated from public databases. We performed random survival forest analysis, Kaplan-Meier (KM) analysis of best combinations, and Cox regression analysis on 231 ferroptosis-related genes to construct a gene signature in the discovery cohort (TCGA), and later validated it in the validation cohort (GEO). The 7-gene signature was constructed to stratify patients into two groups according to their level of risk. Poorer overall survival (OS) was detected in the high risk (HRisk) group than in the low risk (LRisk) group in both the TCGA cohort (P < 0.0001, HR = 1.71, 95%CI:1.41-2.07) and the GEO cohort (P < 0.001, HR = 1.68, 95%CI:1.32-2.13). The risk score was identified as an independent predictive factor of OS in multivariate Cox regression analyses (HR > 1, P < 0.0001) in both cohorts. The signature's predictive capacity was proven by the time-dependent receiver operating characteristic (ROC) curve analysis and nomogram analysis. Functional enrichment analysis revealed that immunosuppressive pathways such as matrix extracellular space, and (transforming growth factor-β)TGF-β were enriched. The HRisk group was strongly associated with upregulation of both cancer-related pathways and stromal scores, while higher proportions of anti-tumor immune cells and immune signatures were enriched in the LRisk group. In conclusion, the signature based on 7 ferroptosis-related genes could be applicable for predicting the prognosis of HNSCC, indicating that ferroptosis may be a potential therapeutic target for HNSCC.

He F ，Chen Z ，Deng W ，Zhan T ，Huang X ，Zheng Y ，Yang H ... -  《-》

Identification novel prognostic signatures for Head and Neck Squamous Cell Carcinoma based on ceRNA network construction and immune infiltration analysis.

Background: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high mortality and morbidity worldwide, but the underlying biological mechanisms of molecules and tumor infiltrating-immune cells (TIICs) are still unknown. Methods and Results: We obtained mRNAs, lncRNAs, and miRNAs expression profiles of 546 HNSCC from The Cancer Genome Atlas (TCGA) database to develop a ceRNA network. CIBERSORT was employed to estimate the fraction of 22 types of TIICs in HNSCC. Univariate and multivariate Cox regression and lasso regression analyses were used to develop prognostic signatures. Then, two novel risk signatures were constructed respectively based on six ceRNAs (ANLN, KIT, PRKAA2, NFIA, PTX3 and has-miR-148a-3p) and three immune cells (naïve B cells, regulatory T cells and Neutrophils). Kaplan-Meier (K-M) analysis and Cox regression analysis further proved that these two signatures were significant prognostic factors independent of multiple clinicopathological characteristics. Two nomograms were built based on ceRNAs-riskScore and TIICs-riskScore that could be used to predict the prognosis of HNSCC. Co-expression analysis showed significant correlations between miR-148a-3p and naive B cells, naive B cells and plasmas cells. Conclusion: Through construction of the ceRNA network and estimation of TIICs, we established two risk signatures and their nomograms with excellent utility, which indicated the potential molecular and cellular mechanisms, and predicted the prognosis of HNSCC.

Zhou H ，He Y ，Li L ，Wu C ，Hu G ... -  《International Journal of Medical Sciences》