Identification and verification of eight cancer-associated fibroblasts related genes as a prognostic signature for head and neck squamous cell carcinoma.

Cancer-associated fibroblasts (CAFs) can exert their immunosuppressive effects by secreting various effectors that are involved in the regulation of tumor-infiltrating immune cells as well as other immune components in the tumor immune microenvironment (TIME), thereby promoting tumorigenesis, progression, metastasis, and drug resistance. Although a large number of studies suggest that CAFs play a key regulatory role in the development of head and neck squamous cell carcinoma (HNSCC), there are limited studies on the relevance of CAFs to the prognosis of HNSCC. In this study, we identified a prognostic signature containing eight CAF-related genes for HNSCC by univariate Cox analysis, lasso regression, stepwise regression, and multivariate Cox analysis. Our validation in primary cultures of CAFs from human HNSCC and four human HNSCC cell lines confirmed that these eight genes are indeed characteristic markers of CAFs. Immune cell infiltration differences analysis between high-risk and low-risk groups according to the eight CAF-related genes signature hinted at CAFs regulatory roles in the TIME, further revealing its potential role on prognosis. The signature of the eight CAF-related genes was validated in different independent validation cohorts and all showed that it was a valid marker for prognosis. The significantly higher overall survival (OS) in the low-risk group compared to the high-risk group was confirmed by Kaplan-Meier (K-M) analysis, suggesting that the signature of CAF-related genes can be used as a non-invasive predictive tool for HNSCC prognosis. The low-risk group had significantly higher levels of tumor-killing immune cell infiltration, as confirmed by CIBERSORT analysis, such as CD8+ T cells, follicular helper T cells, and Dendritic cells (DCs) in the low-risk group. In contrast, the level of infiltration of pro-tumor cells such as M0 macrophages and activated Mast cells (MCs) was lower. It is crucial to delve into the complex mechanisms between CAFs and immune cells to find potential regulatory targets and may provide new evidence for subsequently targeted immunotherapy. These results suggest that the signature of the eight CAF-related genes is a powerful indicator for the assessment of the TIME of HNSCC. It may provide a new and reliable potential indicator for clinicians to predict the prognosis of HNSCC, which may be used to guide treatment and clinical decision-making in HNSCC patients. Meanwhile, CAF-related genes are expected to become tumor biomarkers and effective targets for HNSCC.

Dong L ，Sun Q ，Song F ，Song X ，Lu C ，Li Y ，Song X ... -  《Heliyon》

Construction and validation of a prognostic model based on stage-associated signature genes of head and neck squamous cell carcinoma: a bioinformatics study.

Head and neck squamous cell carcinoma (HNSCC) is a malignancy of epithelial origin and with poor prognosis. Exploring the biomarkers and prognostic models that can contribute to early tumor detection is meaningful. A comprehensive analysis was conducted according to the stage-related signature genes of HNSCC, and a prognostic model was developed to validate their ability to predict the prognosis. The transcriptome profiles and clinical information of HNSCC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) respectively. mRNA expressions of differentially expressed genes (DEGs) were analyzed in stage I-II patients and stage III-IV patients from TCGA by R packages. A protein-protein interaction (PPI) network and core-gene network map were constructed, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to examine pathway enrichment. Kaplan-Meier, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression were applied to establish a stage-associated signature model. A Spearman analysis was conducted to examine the correlations between the characteristic genes and immune cell infiltration. Kaplan-Meier analysis and a receiver operating characteristic (ROC) curve were used to test the effectiveness of the model. Univariate multivariate Cox regression analyses were used to assess whether the risk score was an independent prognostic indicator for HNSCC. In TCGA cohort, 5 genes (i.e., BRINP1, IL17A, ALB, FOXA2, and ZCCHC12) in the constructed prognostic risk model were associated with prognosis. Patients in the low-risk group had a better prognosis outcome than those in the high-risk group. The predictive power was good because all the area under the curve (AUC) of the risk score was higher than 0.6. Risk score [hazard ratio (HR) =1.985; P<0.001] was an independent risk factor for the prognosis of HNSCC. The results in the GEO cohort were consistent with those in the TCGA cohort. We constructed and verified a prognostic risk model of stage-related signature genes for HNSCC based on the GEO and TCGA data. Due to the good predictive accuracy of this model, the prognosis of and the tumor immune cell infiltration with patients can be estimated.

Chen L ，Zhang X ，Lin J ，Wen Y ，Chen Y ，Chen CB ... -  《-》

Integrated single-cell and bulk RNA sequencing analyses reveal a prognostic signature of cancer-associated fibroblasts in head and neck squamous cell carcinoma.

Objectives: To identify a prognosis-related subtype of cancer-associated fibroblasts (CAFs) in head and neck squamous cell carcinoma (HNSCC) and comprehend its contributions to molecular characteristics, immune characteristics, and their potential benefits in immunotherapy and chemotherapy for HNSCC. Materials and Methods: We performed single-cell RNA sequencing (scRNA-seq) analysis of CAFs from the samples of HNSCC patients derived from Gene Expression Omnibus (GEO), to identify the prognosis-related subtype of CAFs. CAFs were clustered into five subtypes, and a prognosis-related subtype was identified. Univariate and multivariate cox regression analyses were performed on the cohort selected from The Cancer Genome Atlas (TCGA) to determine signature construction, which was validated in GSE65858 and GSE42743. A prognostic signature based on 4 genes was constructed, which were derived from prognosis-related CAFs. The molecular characteristics, immune characteristics as well as the predicted chemosensitivity and immunotherapeutic response in the signature-defined subgroups were analyzed subsequently. Results: The patients with higher CAF scores correlated with poor survival outcomes. Additionally, a high CAF score correlated with lower infiltration levels of many immune cells including M1 macrophages, CD8+ T cells, follicular T helper cells, monocytes, and naïve B cells. High CAF score also demonstrated different enrichment pathways, mutation genes and copy number variated genes. Furthermore, patients with high CAF scores showed lower sensitivity for chemotherapy and immunotherapy than those with low CAF scores. Conclusion: The results of our study indicate the potential of the CAF signature as a biomarker for the prognosis of HNSCC patients. Furthermore, the signature could be a prospective therapeutic target in HNSCC.

Yang Y ，Ma B ，Han L ，Xu W ，Du X ，Wei W ，Liao T ，Ji Q ，Qu N ，Wang Y ... -  《Frontiers in Genetics》

Seven Immune-Related Genes' Prognostic Value and Correlation with Treatment Outcome in Head and Neck Squamous Cell Carcinoma.

Mu R ，Shen Y ，Guo C ，Zhang X ，Yang H ，Yang H ... -  《-》

The Aging-Related Prognostic Signature Reveals the Landscape of the Tumor Immune Microenvironment in Head and Neck Squamous Cell Carcinoma.

Numerous studies have shown that the aging microenvironment played a huge impact on tumor progression. However, the clinical prognostic value of aging-related risk signatures and their effects on the tumor immune microenvironment (TIME) in head and neck squamous cell carcinoma (HNSCC) remains largely unclear. This study aimed to identify novel prognostic signatures based on aging-related genes (AGs) and reveal the landscape of the TIME in HNSCC. Differentially expressed AGs were identified using the gene set enrichment analysis (GSEA). The prognostic risk model of AGs was established by univariate and multivariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. The independent prognostic value of the risk model and the correlations of the prognostic signature with immune score, tumor immune cell infiltration, and immune checkpoints were systematically analyzed. A prognostic risk model of four AGs (BAK1, DKK1, CDKN2A, and MIF) was constructed and validated in the training and testing datasets. Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curve analysis confirmed that the four-AG risk signature possessed an accurate predictive value for the prognosis of patients with HNSCC. Correlation analysis revealed that the risk score was negatively associated with immune score and immune cell infiltration level while positively correlated with immune checkpoint blockade (ICB) response score. Patients of the high-risk subtype contained higher infiltration levels of resting natural killer (NK) cells, M0 macrophages, M2 macrophages, and resting mast cells while having lower infiltration levels of memory B cells, CD8+ T cells, follicular helper T cells, regulatory T cells (Tregs), and activated mast cells than did those of the low-risk subtype. The expressions of CTLA4, PDCD1, and TIGIT were downregulated while the PDCD1LG2 expression was upregulated in the high-risk subtype compared to those in the low-risk subtype. Furthermore, the four selected AGs in the risk model were demonstrated to possess important functions in immune cell infiltration and ICB response of HNSCC. The aging-related risk signature is a reliable prognostic model for predicting the survival of HNSCC patients and provides potential targets for improving outcomes of immunotherapy.

Chen F ，Gong X ，Xia M ，Yu F ，Wu J ，Yu C ，Li J ... -  《Frontiers in Oncology》