Characterization of tumor immune microenvironment and cancer therapy for head and neck squamous cell carcinoma through identification of a genomic instability-related lncRNA prognostic signature

Abstract

Head and neck squamous cell carcinoma (HNSCC) represents one of the most prevalent and malignant tumors of epithelial origins with unfavorable outcomes. Increasing evidence has shown that dysregulated long non-coding RNAs (lncRNAs) correlate with tumorigenesis and genomic instability (GI), while the roles of GI-related lncRNAs in the tumor immune microenvironment (TIME) and predicting cancer therapy are still yet to be clarified. In this study, transcriptome and somatic mutation profiles with clinical parameters were obtained from the TCGA database. Patients were classified into GI-like and genomic stable (GS)-like groups according to the top 25% and bottom 25% cumulative counts of somatic mutations. Differentially expressed lncRNAs (DElncRNAs) between GI- and GS-like groups were identified as GI-related lncRNAs. These lncRNA-related coding genes were enriched in cancer-related KEGG pathways. Patients totaling 499 with clinical information were randomly divided into the training and validation sets. A total of 18 DElncRNAs screened by univariate Cox regression analysis were associated with overall survival (OS) in the training set. A GI-related lncRNA signature that comprised 10 DElncRNAs was generated through least absolute shrinkage and selection operator (Lasso)-Cox regression analysis. Patients in the high-risk group have significantly decreased OS vs. patients in the low-risk group, which was verified in internal validation and entire HNSCC sets. Integrated HNSCC sets from GEO confirmed the notable survival stratification of the signature. The time-dependent receiver operating characteristic curve demonstrated that the signature was reliable. In addition, the signature retained a strong performance of OS prediction for patients with various clinicopathological features. Cell composition analysis showed high anti-tumor immunity in the low-risk group which was evidenced by increased infiltrating CD8+ T cells and natural killer cells and reduced cancer-associated fibroblasts, which was convinced by immune signatures analysis via ssGSEA algorithm. T helper/IFNγ signaling, co-stimulatory, and co-inhibitory signatures showed increased expression in the low-risk group. Low-risk patients were predicted to be beneficial to immunotherapy, which was confirmed by patients with progressive disease who had high risk scores vs. complete remission patients. Furthermore, the drugs that might be sensitive to HNSCC were identified. In summary, the novel prognostic GILncRNA signature provided a promising approach for characterizing the TIME and predicting therapeutic strategies for HNSCC patients.

Comprehensive Transcriptome Analysis Reveals the Distinct Gene Expression Patterns of Tumor Microenvironment in HPV-Associated and HPV-Non Associated Tonsillar Squamous Cell Carcinoma

“…To gain a more comprehensive understanding of the gene expression in the TME of HPV-associated and non-associated TSCC, we focused on the gene expression profiling of 168 genes that are linked to the communication between tumor cells and the cellular mediators of inflammation and immunity, oncogenesis promotion, tumor suppressor genes, transcription factors, angiogenesis, and apoptosis. The TME of HNSCC is a crucial factor in achieving effective cancer therapy [20,21]. The TME is heterogeneous and complex, consisting of a variety of cell types, including cancer-associated fibroblasts, diverse immune cells, and non-cell extracellular matrix components [22,23,34].…”

“…The TME can also affect the outcome of cancer immunotherapy by modulating immune cell infiltration and/or activation [27]. Characterizing the TME of HNSCC has identified TME as a heterogeneous environment [20]. Different factors could lead to changes in gene expression patterns in the TME of HNSCC [21].…”

“…Some studies have studied the TME of HNSCC and identified important gene signatures as prognostic and immunotherapeutic targets [23]. In addition, the dysregulation of various genes in HNSCC patients has been associated with reduced overall survival [20].…”

“…The tumor microenvironment (TME) of HNSCC is a crucial factor in achieving effective cancer therapy [6,20,21]. The TME of HNSCC is heterogeneous and complex, consisting of a variety of cell types, including cancer-associated fibroblasts, diverse immune cells, and noncell extracellular matrix components [22,23].…”

Molecular Signature of Long Non-Coding RNA Associated with Areca Nut-Induced Head and Neck Cancer

“…Based on this dataset, several lncRNA profiles associated with specific carcinogenic attributes were constructed. These include the effects of alcohol consumption [ 26 ], human papillomavirus infection [ 27 ], immunity or tumor microenvironment [ 28 , 29 ], and their association with prognosis [ 29 , 30 , 31 , 32 , 33 ]. However, most studies solely analyzed big data without further experimental validation, which may limit the pathological insight of candidate molecules.…”