The Emerging Role of MTHFD Family Genes in Regulating the Tumor Immunity of Oral Squamous Cell Carcinoma

OBJECTIVE: To investigate the function and regulatory mechanisms of methylenetetrahydrofolate dehydrogenase (MTHFD) family genes in oral squamous cell carcinoma (OSCC), especially focus on their regulating role in tumor immunity. METHODS: The publicly available data from the TCGA database were used to investigate the expression pattern and regulatory role of MTHFD family genes in OSCC. More importantly, the involvement of MTHFD family genes in tumor immunity was investigated in terms of immune and stromal cell infiltration in tumor microenvironment, tumor-infiltrating immune cells, and immunomodulatory genes (e.g., immunoinhibitory genes and immunostimulatory genes). Statistical analysis was performed using R software packages and public web servers. RESULTS: MTHFD family genes were considerably upregulated in OSCC as compared with normal oral tissue. Patients with high MTHFD2 expression presented worse survival outcomes than those with low MTHFD2 expression. Functional enrichment analysis showed that the top 100 positively and negatively correlated genes of the MTHFD family genes were significantly enriched in several KEGG pathways, including cell cycle, spliceosome, DNA replication, and Th17 cell differentiation. As a result of tumor immunity analysis, MTHFD2L expression was found to be negatively related to the Estimate-Stromal-Immune score in OSCC; however, there was no statistical significance between the Estimate-Stromal-Immune score and MTHFD1, MTHFD1L, or MTHFD2 in OSCC. Additionally, MTHFD family genes were found to be significantly positively correlated with tumor-infiltrating immune cells, including Treg and Th17 cells. Moreover, MTHFD family genes were significantly correlated with several immune inhibitory genes such as CD274 and CTLA4 and several immune-stimulatory genes such as CXCL12, CXCR4, and TMIGD2. CONCLUSION: Given the expression pattern, prognostic value, biological functions, and involvement in tumor immunity, MTHFD family genes could serve as potential therapeutic biomarkers in targeting tumor immunity in oral cancer.