EGFR Inhibition by Cetuximab Modulates Hypoxia and IFN Response Genes in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) has one of the most hy-poxic and immunosuppressive tumor microenvironments (TME) among solid tumors. However, there is no proven therapeutic strategy to re-model the TME to be less hypoxic and proinflammatory. In this study, we classified tumors according to a Hypoxia-Immune signature, charac-terized 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 num-bers of immunosuppressive cells, as evidenced by a lower ratio of CD8+ T cells to FOXP3+ regulatory T cells, compared with nonhypoxic 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 EGFR and TGF & beta; pathway genes. Ce-tuximab, 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. Significance: While the hypoxic and immunosuppressive TME of HNSCC has been well described, comprehensive evaluation of the immune cell com-ponents and signaling pathways contributing to immunotherapy resistance has been poorly characterized. We further identified additional molecular determinants and potential therapeutic targets of the hypoxic TME to fully leverage currently available targeted therapies that can be administered with immunotherapy.

Automated summary

In this study, the researchers classified tumors based on a Hypoxia-Immune signature, identified immunosuppressive cells in hypoxic tumors, and analyzed signaling pathways to find a potential therapeutic target to remodel the tumor microenvironment. They found that hypoxic tumors had more immunosuppressive cells and worse outcomes after treatment with certain immune inhibitors. The use of an anti-EGFR inhibitor showed promise in remodeling the hypoxic tumor microenvironment. This study provides a rationale for combining EGFR-targeted agents and immunotherapy in the management of hypoxic HNSCC.