Labiano Sara, Palazon Asis, Melero Ignacio
Oncology and Immunology Department, CIMA, Pamplona, Spain.
Physiological Laboratory, Department of PDN, University of Cambridge, Cambridge, UK.
Semin Oncol. 2015 Jun;42(3):378-86. doi: 10.1053/j.seminoncol.2015.02.009. Epub 2015 Feb 13.
Lymphocytes and myeloid cells sense hypoxia by the hypoxia-inducible factor (HIF) transcriptional system and via other molecular mechanisms. Low O2 availability is a hallmark of most solid tumors in which infiltrating leukocytes experience severe hypoxia once away from nurturing blood vessels. HIF controls migration, differentiation, and effector functions on immune cells. Importantly, in the tumor microenvironment the hypoxia response modulates the expression levels for important molecular targets in immunotherapy such as CD137, OX-40, FOXP3, and PD-L1. Modulation by hypoxia of tumor-associated macrophages, myeloid-derived suppressor cells, and dendritic cells ought to play an important underexplored role in modulating tumor immunity. Overall, low O2 seems to invigorate some anti-tumor effector T-cell functions while conflictingly favoring T-regulatory cells (Tregs) in terms of their differentiation, suppressive functions, and recruitment. Hypoxia also has been shown to uphold myeloid cell-mediated tumor-promoting inflammation and the immunosuppressive functions of tumor-associated macrophages. Detailed research of this intricate and poorly understood balance is warranted to improve the outcome of cancer immunotherapy.
淋巴细胞和髓样细胞通过缺氧诱导因子（HIF）转录系统及其他分子机制感知缺氧。低氧可用性是大多数实体瘤的一个标志，在实体瘤中，浸润的白细胞一旦远离滋养血管就会经历严重缺氧。HIF控制免疫细胞的迁移、分化和效应功能。重要的是，在肿瘤微环境中，缺氧反应调节免疫治疗中重要分子靶点的表达水平，如CD137、OX - 40、FOXP3和PD - L1。缺氧对肿瘤相关巨噬细胞、髓源性抑制细胞和树突状细胞的调节，在调节肿瘤免疫方面应该起着重要但尚未充分探索的作用。总体而言，低氧似乎能增强一些抗肿瘤效应T细胞的功能，而在T调节细胞（Tregs）的分化、抑制功能和募集方面却又矛盾地对其有利。缺氧还被证明能维持髓样细胞介导的肿瘤促进炎症以及肿瘤相关巨噬细胞的免疫抑制功能。有必要对这种复杂且了解不足的平衡进行详细研究，以改善癌症免疫治疗的效果。
