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Supplementary Figure S4 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma

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posted on 2023-05-04, 14:00 authored by Ritu Chaudhary, Robbert J.C. Slebos, Leenil C. Noel, Feifei Song, Maria I. Poole, Dirk S Hoening, Juan C. Hernandez-Prera, Jose R Conejo-Garcia, Jose Alejandro Guevara, Xuefeng Wang, Mengyu Xie, Aik Choon Tan, Christine H. Chung

(A-C) Clinical Proteomic Tumor Analysis Consortium head and neck squamous cell carcinoma cohort. The gene expressions were compared for pathways enriched in: (A) Immune vs Hypoxia. Red: enriched in Immune, Blue: enriched in Hypoxia. (B) Immune vs Mixture. Red: enriched in Immune, Blue: enriched in Mixture. (C) Hypoxia vs Mixture. Red: enriched in Hypoxia, Blue: enriched in Mixture. Indicated are the top 10 most differentially expressed pathways in Cancer Hallmarks gene sets. NES: Normalized Enrichment Score

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ARTICLE ABSTRACT

Head 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.