Protein network analysis of core-enriched genes within the hypoxia signature and TGF-β signaling from GSEA analysis. Clustering was performed using the STRING database. Three main clusters are depicted: hypoxia (blue color), TGF-β (green color), and EGFR (red color).
ARTICLE ABSTRACTHead and neck squamous cell carcinoma (HNSCC) has one of the most hypoxic and immunosuppressive tumor microenvironments (TME) among solid tumors. However, there is no proven therapeutic strategy to remodel the TME to be less hypoxic and proinflammatory. In this study, we classified tumors according to a Hypoxia-Immune signature, characterized the immune cells in each subgroup, and analyzed the signaling pathways to identify a potential therapeutic target that can remodel the TME. We confirmed that hypoxic tumors had significantly higher numbers of immunosuppressive cells, as evidenced by a lower ratio of CD8+ T-cells to FOXP3+ regulatory T-cells, compared to non-hypoxic tumors. Patients with hypoxic tumors had worse outcomes after treatment with pembrolizumab or nivolumab, anti-Programmed Cell Death-1 inhibitors. Our expression analysis also indicated that hypoxic tumors predominantly increased the expression of the epidermal growth factor receptor (EGFR) and transforming growth factor-β pathway genes. Cetuximab, an anti-EGFR inhibitor, decreased the expression of hypoxia signature genes, suggesting that it may alleviate the effects of hypoxia and remodel the TME to become more proinflammatory. Our study provides a rationale for treatment strategies combining EGFR-targeted agents and immunotherapy in the management of hypoxic HNSCC.