Abstract
e18019 Background: Head and neck squamous cell carcinoma (HNSCC) that has metastasized presents a significant challenge for cancer treatment, requiring innovative approaches to predict immunotherapy response. Methyltransferase-like 3 (METTL3), a key component of the m6A RNA methylation machinery, has been shown to have various roles in cancer, including its potential impact on immunotherapy responses. In this study, we aim to explore the expression and related function of METTL3 in metastatic HNSCC. Methods: We investigated the expression level and its clinicopathological significance of METTL3 using The Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (TCGA-HNSC) datasets. Further validation of the METTL3 mRNA and protein expression were carried out with real-time PCR and Western blot on tissues from 112 cases of HNSCC patients. In addition, the functional role of METTL3 was investigated in vitro studies. The treatment response prediction values of METTL3 in metastatic HNSCC were calculated using ROC-plotter. Results: Our investigation revealed a significant overexpression of METTL3 in HNSCC tissue samples than in normal tissues ( p < 0.001). The high expression of METTL3 was significantly correlated with nodal metastasis, advanced cancer stages, and higher tumor grades in HNSCC samples, indicating that METTL3 plays an important role in driving HNSCC progression and aggressiveness. The functional study revealed intricate connections between METTL3 and immune regulatory genes expression, highlighting its potential to influence the tumor immune microenvironment. Silencing or pharmacological inhibition of METTL3 by METTL3 inhibitor STM2457 reduced tumorigenic activity through decreasing PD-L1 expression. ROC-plotter calculations showed that the high METTL3 expression predicted powerful immunotherapy (AUC=0.588, p=6.3e-06) in metastatic HNSCC patients. Conclusions: In conclusion, METTL3 appears to be a promising predictive biomarker for the response to immunotherapy in patients with metastatic HNSCC. This research provides valuable insights into the multifaceted role of METTL3 and promising therapeutic response predictor in metastatic HNSCC.
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