Causal role of immune cells in head and neck squamous cell carcinoma

Chronic inflammation, immune cell infiltration, and metabolic reprogramming play a crucial role in the development of head and neck squamous cell carcinoma (HNSCC). Based on the summary-level data from a genome-wide association study (GWAS), this study used Mendelian randomization (MR) analysis to investigate the causal relationship between immune cell phenotype and HNSCC. Two-step MR was employed to quantify the proportion of the effect of metabolite-mediated immunophenotypes on HNSCC. 16 immune phenotypes exhibited a causal relationship with HNSCC. HLA DR + CD4 + AC (OR: 1.31, 95% CI 1.07-1.59, P < 0.01) and EM CD8br AC cells (OR: 1.36, 95% CI 1.14-1.62, P < 0.01) showed the most significant P values. 13 metabolites have a causal relationship with HNSCC (P < 0.05). The proportion of the effect of Bilirubin degradation product, C16H18N2O5 (3) levels-mediated HLA DR + CD4 + AC on HNSCC was 7.17% (95% CI 1.04%-13.3%), while the proportion of the effect of Glutamine to alanine ratio-mediated EM CD8br AC on HNSCC was 8.88% (95% CI 2.2%-15.6%). Moreover, single-cell RNA-sequencing analysis confirmed that HLA DR + CD4 + AC and EM CD8br AC cells were commonly present in the HNSCC tumor microenvironment (TME). High expression of two immune phenotypes indicated a poorer prognosis. The results of differentially expressed genes (DEGs) analysis and functional enrichment indicated that Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)/Follicular dendritic cell secreted protein (FDCSP) and Keratin 19 type I (KRT19)/Kallikrein-related peptidase 5 (KLK5) may be responsible genes for two immune phenotypes, respectively. The results of quantitative real-time polymerase chain reaction (qRT-PCR) and survival analysis showed that FDCSP was significantly downregulated in HNSCC and could exert a protective effect. Collectively, our study clarified the causal relationship between immune cells, metabolites, and HNSCC, providing new insight for clinical diagnosis and treatment of HNSCC.