Francis Amirtharaj, Venkatesh Goutham Hassan, Zaarour Rania Faouzi, Zeinelabdin Nagwa Ahmed, Nawafleh Hussam H, Prasad Prathibha, Buart Stéphanie, Terry Stéphane, Chouaib Salem
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates.
INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Faculty de Médecine University Paris-Sud, University Paris-Saclay, Villejuif F-94805, France.
Crit Rev Immunol. 2018;38(6):505-524. doi: 10.1615/CritRevImmunol.2019030168.
Recent antitumor immunotherapies such as monoclonal antibodies targeting immune checkpoints have led to outstanding results in several cancers. However, despite the favorable outcomes for responding patients, the response rate remains relatively low. This is in part due to the influence of the tumor microenvironment (TME) in protecting the tumor from the antitumor immune response and facilitating immune escape. Tumor hypoxia is one of the most important features of the TME, exerting an adverse effect on tumor aggressiveness and patient prognosis. Hypoxic stress interferes with immune plasticity and promotes tumor heterogeneity and progression. Cellular adaptation to hypoxia is primarily mediated by a family of transcriptional regulators, hypoxia-inducible factor (HIF). Apart from hypoxia, the HIF pathway is modulated in a hypoxia-independent manner. HIF-1α stabilization and activity are regulated by epigenetic changes and mutations. Strong evidence indicates that tumor hypoxia controls malignant and metastatic phenotype of cancer cells and therefore presents a unique therapeutic challenge in the treatment of solid malignancies. An alluring alternative strategy to reinvigorate anticancer immune responses comes from the emerging field of TME and its associated pathways. Targeting hypoxia or its associated pathways may therefore offer new options in the design of innovative cancer immunotherapy approaches. In this article, we briefly review the potential of hypoxic stress on tumor plasticity and stromal reactivity as well as the possible targeting of hypoxia-induced pathways to increase immunotherapy efficiency.
近期的抗肿瘤免疫疗法，如靶向免疫检查点的单克隆抗体，已在多种癌症中取得了显著成效。然而，尽管对有反应的患者疗效良好，但总体缓解率仍然相对较低。部分原因在于肿瘤微环境（TME）对肿瘤的保护作用，使其免受抗肿瘤免疫反应的影响，并促进免疫逃逸。肿瘤缺氧是TME的最重要特征之一，对肿瘤侵袭性和患者预后产生不利影响。缺氧应激会干扰免疫可塑性，促进肿瘤异质性和进展。细胞对缺氧的适应主要由一类转录调节因子——缺氧诱导因子（HIF）介导。除了缺氧，HIF通路还以不依赖缺氧的方式受到调节。HIF-1α的稳定性和活性受表观遗传变化和突变的调控。有力证据表明，肿瘤缺氧控制着癌细胞的恶性和转移表型，因此在实体恶性肿瘤的治疗中提出了独特的治疗挑战。一种重振抗癌免疫反应的诱人替代策略来自新兴的TME及其相关通路领域。因此，靶向缺氧或其相关通路可能为创新癌症免疫治疗方法的设计提供新的选择。在本文中，我们简要回顾了缺氧应激对肿瘤可塑性和基质反应性的潜在影响，以及靶向缺氧诱导通路以提高免疫治疗效率的可能性。
