Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, Florida.
Department of Pathology, Moffitt Cancer Center, Tampa, Florida.
Cancer Res Commun. 2023 May 22;3(5):896-907. doi: 10.1158/2767-9764.CRC-22-0443. eCollection 2023 May.
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 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 TGFβ 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.
While the hypoxic and immunosuppressive TME of HNSCC has been well described, comprehensive evaluation of the immune cell components 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.
头颈部鳞状细胞癌（HNSCC）是实体瘤中缺氧和免疫抑制肿瘤微环境（TME）最严重的肿瘤之一。然而，目前还没有经过验证的治疗策略来重塑 TME，使其缺氧程度降低和炎症反应增强。在这项研究中，我们根据缺氧-免疫特征对肿瘤进行分类，描述了每个亚组中的免疫细胞，并分析了信号通路，以确定一种潜在的治疗靶点，重塑 TME。我们证实，与非缺氧性肿瘤相比，缺氧性肿瘤具有显著更高数量的免疫抑制细胞，这表现在 CD8 T 细胞与 FOXP3 调节性 T 细胞的比例较低。与接受抗程序性细胞死亡-1 抑制剂 pembrolizumab 或 nivolumab 治疗的患者相比，患有缺氧性肿瘤的患者在治疗后预后更差。我们的表达分析还表明，缺氧性肿瘤主要增加了 EGFR 和 TGFβ 通路基因的表达。抗 EGFR 抑制剂 cetuximab 降低了缺氧特征基因的表达，这表明它可能减轻缺氧的影响并重塑 TME，使其更具炎症反应性。我们的研究为联合 EGFR 靶向药物和免疫治疗治疗缺氧性 HNSCC 的治疗策略提供了依据。
尽管 HNSCC 的缺氧和免疫抑制 TME 已经得到了很好的描述，但对导致免疫治疗耐药的免疫细胞成分和信号通路的全面评估仍描述不足。我们进一步确定了缺氧 TME 的其他分子决定因素和潜在治疗靶点，以充分利用目前可与免疫治疗联合使用的靶向治疗药物。
