Abstract
Metabolic dysregulation has emerged as a crucial determinant of the clinical responses to immunotherapy. The aim of this study was to determine the clinical significance of the candidate immune-related metabolic enzymes (IRMEs) methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 (MTHFD2) in head and neck squamous cell carcinoma (HNSCC). The gene expression profile of HNSCC cohort and the corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA). The differentially expressed IRMEs were identified, and then, the prognosis-associated IRMEs were revealed by univariate cox regression analysis. The prognostic significance of MTHFD2 in HNSCC as well as the association between MTHFD2 and immune cell infiltration were further analyzed. A total of 121 significantly altered IRMEs were identified between HNSCC and normal tissues, and 21 IRMEs were found to be strongly associated with overall survival of HNSCC. Upregulation of MTHFD2 was positively correlated with adverse clinicopathological factors in TCGA HNSCC cohort, which was further validated with our own cohort using immunohistochemical analysis. Interestingly, bioinformatic analysis further revealed that increased MTHFD2 expression was negatively associated with NK cells activation, while positively correlated with mast cells activation. In conclusion, MTHFD2 overexpression is closely correlated with unfavorable prognosis of HNSCC, and it might play an important role in modulating the tumor immune microenvironment.
Highlights
Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common malignancy around the world [1,2,3]
Bioinformatic analysis of the significantly altered metabolic enzymes revealed many important metabolic pathways were deregulated in HNSCC
It is widely observed that many cancer cells display enhanced glycolytic activity and suppressed mitochondrial metabolism [14], which is consistent with our findings that glycolysis/gluconeogenesis was the top enriched pathway in HNSCC
Summary
Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common malignancy around the world [1,2,3]. It arises in the oral cavity, oropharynx, hypopharynx, and larynx [4]. Radiotherapy, chemotherapy, and targeted therapy remain the major treatment modalities for HNSCC. Accurate prediction of HNSCC prognosis is of great importance for successful clinical management and individualized medicine. The Tumor, Node, Metastasis (TNM) staging system for HNSCC is still the most widely used prognostic indicator in clinical practice. The HNSCC cases with the same TNM stage might have significantly different clinical outcomes
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