Abstract
Purpose: We systematically analyzed HNSCC-infiltrating T lymphocytes lncRNAs (HILTlncRNAs) to assess their predictive value for the survival outcome and immunotherapy response of patients with anti-programmed death-1 (PD-1) therapy and to evaluate their predictive power to chemotherapeutic agents. Methods: HNSCC transcriptome and clinical information was obtained from The Cancer Genome Atlas (TCGA) database. Immunocell microarray data were obtained from the Gene Expression Omnibus (GEO) database. T-cell-specific lncRNAs were identified by differential expression analysis. Prognostic paired HILTlncRNAs (PHILTlncRNAs) were filtered and modeled by univariate cox, lasso and multivariate cox regression analysis. To construct lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory networks, differentially expressed mRNAs in HNSCC patients were incorporated, microRNAs and differentially expressed mRNAs interacting with T-cell-specific lncRNAs were filtered out based on miRcode, miRDB, miRTarBase, and TargetScan databases. Results: 75 T-cell-specific lncRNAs and 9 prognostic PHILTlncRNAs were identified. Low-risk HNSCC patients had a better prognosis and significant immune cell infiltration, driving the immune response. Differential expression of RNA-binding proteins (RBPs), PD-1 and programmed cell death 1 ligand 1 (PD-L1) was demonstrated in the high and low risk groups of HNSCC patients. In the high risk group, high expression of PD-1 improved patient prognosis, whereas the opposite was observed in the low-risk group. The promoter methylation levels of two RBPs (DNMT1 and ZC3H12D) were decreased in HNSCC patients compared with normal samples, their expression levels were positively correlated with PD-1 and PD-L1 levels and T-cell infiltration. Finally, we screened the sensitivity of HNSCC patients to chemotherapeutic agents and found it differed between high and low risk groups. Conclusion: HILTlncRNAs provided a theoretical basis for immune targeted therapy and drug development.
Highlights
Head and neck squamous cell carcinoma (HNSCC) occurs mainly in the mucosal epithelium of the pharynx and oral cavity
In the high risk group, high expression of programmed death-1 (PD-1) improved patient prognosis, whereas the opposite was observed in the low-risk group
The promoter methylation levels of two RNA-binding proteins (RBPs) (DNMT1 and ZC3H12D) were decreased in HNSCC patients compared with normal samples, their expression levels were positively correlated with PD-1 and programmed cell death 1 ligand 1 (PD-L1) levels and T-cell infiltration
Summary
Head and neck squamous cell carcinoma (HNSCC) occurs mainly in the mucosal epithelium of the pharynx and oral cavity. High level of T lymphocyte infiltration in the TME or close to the tumor cell parenchyma may have prognostic value (Lei et al, 2016; Di Martino et al, 2019). High infiltration of CD4+ and CD8+ T cells in the TME has been associated with improved overall and relapse-free survival in patients with HNSCC, and could serve as an independent prognostic factor (Nguyen et al, 2016). Elevated interleukin 23 (IL-23) and IL-6 levels released by HNSCC cells may promote T helper 17 (Th17) cell proliferation (Kesselring et al, 2010), while Th17 and Tregs proliferation is associated with the functional impairment of infiltrating CD8+ T cells in HNSCC (Kesselring et al, 2010; Liu et al, 2018b). Restoring exhausted T cells in the TME by blocking TIGIT/CD155 promotes antitumor immunity in HNSCC (Wu et al, 2019)
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