Department of Radiation Oncology and Radiotherapy, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany.
Center of Translational Cancer Research (TranslaTUM), Technical University of Munich, Campus Klinikum rechts der Isar, Munich, Germany.
Adv Exp Med Biol. 2018;1072:171-175. doi: 10.1007/978-3-319-91287-5_27.
The metabolic tumor microenvironment (TME) is characterized inter alia by critical oxygen depletion (hypoxia/anoxia), extracellular acidosis (pH ≤ 6.8), high lactate levels (up to 40 mM in heterogeneously distributed areas), strongly elevated adenosine concentrations (10-100 μM) and declining nutrient resources. These TME features are major drivers, e.g., for genetic instability, intratumor heterogeneity, malignant progression and development of resistance to conventional anticancer therapies. In this context, hypoxia-dependent (and non-hypoxic) HIF-1α activation plays a key role in orchestrating a multifaceted (local) suppression of innate and adaptive antitumor immune responses (and of immune-based tumor treatment). Besides the characteristic traits mentioned, the immune-suppressive actions can additionally be triggered by an (over-)expression of VEGF and activation of VEGFR, and externalisation of phosphatidylserine from the inner to the outer membrane leaflet of cells and exosomes. Altogether, and even individually, these features provide strong immune-suppressive signals. The downstream effects of an enhanced HIF-1α expression include (a) an activation of immune-suppressive effects (recruitment and stimulation of immune-suppressor cells [e.g., Treg, MDSC], secretion of immune-suppressive TH2-type cytokines), and (b) inhibition of antitumor immune responses (inhibition of immune cell actions [e.g., NK, NKT, CD4, CD8], inhibition of antigen-presenting cells [e.g., DC], reduced production of immune-stimulatory TH1-type cytokines).
肿瘤代谢微环境（TME）的特点包括关键的氧气耗竭（缺氧/乏氧）、细胞外酸中毒（pH 值≤6.8）、高乳酸水平（在异质分布区域高达 40mM）、强烈升高的腺苷浓度（10-100μM）和不断下降的营养资源。这些 TME 特征是遗传不稳定性、肿瘤内异质性、恶性进展和对传统抗癌治疗产生耐药性的主要驱动因素。在这种情况下，缺氧依赖性（和非缺氧依赖性）HIF-1α 激活在协调多方面（局部）抑制先天和适应性抗肿瘤免疫反应（以及基于免疫的肿瘤治疗）方面发挥着关键作用。除了提到的特征外，免疫抑制作用还可以通过 VEGF 的过度表达和 VEGFR 的激活以及细胞内外膜小叶中磷脂酰丝氨酸的外化和外泌体触发。总的来说，这些特征单独或共同提供了强烈的免疫抑制信号。增强的 HIF-1α 表达的下游效应包括：（a）激活免疫抑制作用（招募和刺激免疫抑制细胞[例如 Treg、MDSC]，分泌免疫抑制性 TH2 型细胞因子）；（b）抑制抗肿瘤免疫反应（抑制免疫细胞作用[例如 NK、NKT、CD4、CD8]，抑制抗原呈递细胞[例如 DC]，减少免疫刺激性 TH1 型细胞因子的产生）。
