Lactate metabolism as a dictator of patient outcomes and immune microenvironment in head and neck squamous carcinoma

e18038 Background: Head and neck squamous cell carcinoma (HNSCC) treatment is facing clinical challenges. Recent research reports have highlighted the integral function performed by the tumor microenvironment (TME) in the prediction of clinical outcomes. Lactate metabolism mediates many cancers’ initiation and progression, including metastasis, angiogenesis and immunosuppression. However, the prognostic significance of lactate metabolism-related genes (LMRGs) and the role of TME in HNSCC requires further elucidation. Methods: We built a prognostic multigene signature with LMRGs and systematically correlated the risk signature with immunological characteristics and immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize lactate metabolism in TME.The most important prognostic gene among risk signature was screened by machine learning analysis. Finally, single-cell sequencing analysis, immunofluorescence analyses, and a series of in vitro experiments were used to explore the role of PYGL in HNSCC. Results: LMRGs-related prognostic model showed good prediction performance. The immunological signaling pathways are linked to low-risk scores. Patients in low-risk group were characterized by low levels of lactate metabolism, high levels of CD8+ T cells infiltration, “hot”immune phenotype and benefit from immunotherapy. Compared with other cells, tumor cells in TME exhibited the most active lactate metabolism. Machine learning analysis highlighted that PYGL was the most important prognostic gene among risk signatures. And lactate concentrations decreased in PYGL knockdown cells. We found that PYGL was highly expressed in macrophages, may inhibit the polarization of M1 macrophages. The inflammatory phenotype was characterized by the least expression of PYGL, which was observed to be inversely linked to CD8+ T-cell infiltration, as determined by immunofluorescence analyses. Conclusions: Our study identified and validated a promising LMRGs signature associated with inflamed TME, which may accurately anticipate the survival of HNSCC patients. PYGL might be a novel biomarker to predict immune efficacy.