Abstract
Background Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, which remains a major cause of morbidity and mortality in patients with head and neck cancers. However, the critical immune-related signatures and their prognostic values have rarely been investigated. Materials and Methods Gene differential analysis was used to measure the differences of gene expression between the groups. Correlation analysis was used to assess the association between the gene expression levels and immune-related risk score/DNA methylation levels. The gene set enrichment analysis (GSEA) was used to identify the pathways or cell types enriched by those identified differentially expressed genes (DEGs). Results In this study, we identified four immune-related gene signatures, including CTSG, TNFRSF4, LCORL, and PLAU, that were significantly associated with the overall survival in OSCC patients from the Cancer Genome Atlas (TCGA) OSCC cohort. Moreover, these four immune-related signatures were differentially expressed between the OSCC and nontumor tissues. The two groups (high and low risk) stratified by the immune-related risk scores had significantly different OS and mortality rates. The gene expression patterns and prognostic values of these immune-related signatures were also verified in two independent validation cohorts. Furthermore, the downregulated genes in the high-risk group (which were also upregulated in the low-risk group) were significantly enriched in the cell type-specific signatures of type 2 T helper cell (Th2), plasmacytoid dendritic cell (pDC), and memory B cell. In contrast, the upregulated genes in the high-score group were enriched in growth factor receptor-related signaling pathways, such as the VEGFA-VEGFR2 signaling pathway, PI3K-Akt signaling pathway, focal adhesion-PI3K-Akt-mTOR signaling pathway, and PDGF pathway, suggesting that those pathways were inversely correlated with immune cell infiltration. Conclusion In summary, the immune-related signatures had the potential for predicting the risk of OSCC patients. Moreover, the present study also improved our understanding of the association between the growth factor receptor pathways and immune cell infiltration in OSCC.
Highlights
Oral squamous cell carcinoma (OSCC) constitutes a huge proportion of head and neck malignancies, posing a growing threat to the global public health [1]
Improved prognoses are observed in human papillomavirus (HPV)-positive head and neck cancer patients with a controlled load of tumor-type HPV DNA during therapy, and differences are appreciated in the immune profiles of HPV-positive and HPV-negative patients, as increased expression of a T-regulatory cell (Tregs) marker gene and decreased expression of a M2 protumorigenic macrophage marker gene were observed in HPV-positive head and neck squamous cell carcinoma (HNSCC) compared to HPV-negative tumors [4], hinting that further exploration of the tumor Journal of Immunology Research microenvironment in OSCC shall benefit the identification of prognostic markers and therapeutic targets [5, 6]
Using the lambda.min cutoff threshold, we identified four immune-related gene signatures, including CTSG, TNFRSF4, LCORL, and PLAU, that were significantly associated with overall survival in OSCC patients (Figure 1(a))
Summary
Oral squamous cell carcinoma (OSCC) constitutes a huge proportion of head and neck malignancies, posing a growing threat to the global public health [1]. A recent study has reported 6 immune subtypes in squamous cell carcinomas, each with identical patterns of immunerelated gene expression, and the survival outcomes significantly varied across different subtypes, where similar to previously published research findings, higher levels of immune infiltration are observed to be associated with favorable prognosis, possibly via upregulated pathways that are involved in chemokine and cytokine signaling, T cell survival following inflammation, antigen presentation, and tumor progression [10, 11] Those pathways include IL-2, IL-6, IL-10, CD40, MAPK/ERK, TGFβ, JAK/STAT, and AKT/mTOR pathways; all of which are frequently addressed in varied cancer types.
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