New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, USA.
Adv Exp Med Biol. 2019;1136:113-121. doi: 10.1007/978-3-030-12734-3_8.
Long-term studies of anti-pathogen and anti-tumor immunity have provided complementary genetic and pharmacological evidence for the immunosuppressive and immunomodulatory effects of Hypoxia-HIF-1α and adenosine-mediated suppression via the A2A adenosine receptor signaling pathway (Hypoxia-A2A-adenosinergic). This pathway is life saving when it protects inflamed tissues of vital organs from collateral damage by overactive anti-pathogen immune cells or enables the differentiation of cells of adaptive immunity. However, the Hypoxia-A2A-adenosinergic immunosuppression can also prevent tumor rejection by inhibiting the anti-tumor effects of T and NK cells. In addition, this suppressive pathway has been shown to mask tumors due to the hypoxia-HIF-α-mediated loss of MHC Class I molecules on tumor cells. It is suggested that it will be impossible to realize the full anti-tumor capacities of current cancer immunotherapies without simultaneous administration of anti-Hypoxia-A2A-Adenosinergic drugs that inactivate this tumor-protecting mechanism in hypoxic and adenosine-rich tumors.Here, we overview the supporting evidence for the conceptually novel immunotherapeutic motivation to breathe supplemental oxygen (40-60%) or to repurpose already available oxygenation agents in combination with current immunotherapies. Preclinical studies provide strong support for oxygen immunotherapy to enable much stronger tumor regression by weakening immunosuppression by A2A adenosine receptors and by the Hypoxia➔HIF-1α axis. The results of these studies emphasize the value of systemic oxygenation as clinically feasible, promising, and as a valuable tool for mechanistic investigations of tumor biology and cancer immunology. Perhaps the most effective and feasible among individual members of this novel class of anti-tumor drugs are oxygenation agents.
长期以来，对病原体和抗肿瘤免疫的研究为缺氧-HIF-1α和通过 A2A 腺苷受体信号通路（Hypoxia-A2A-adenosinergic）介导的腺苷抑制的免疫抑制和免疫调节作用提供了互补的遗传和药理学证据。当它保护重要器官的炎症组织免受过度活跃的抗病原体免疫细胞的旁系损伤，或者使适应性免疫细胞分化时，该途径是挽救生命的。然而，Hypoxia-A2A-adenosinergic 免疫抑制也可以通过抑制 T 和 NK 细胞的抗肿瘤作用来阻止肿瘤排斥。此外，由于缺氧-HIF-α介导的肿瘤细胞 MHC Ⅰ类分子丢失，该抑制途径已被证明可以掩盖肿瘤。有人认为，如果不同时给予抗缺氧-A2A-腺苷药物来灭活缺氧和腺苷丰富的肿瘤中的这种肿瘤保护机制，就不可能充分发挥当前癌症免疫疗法的抗肿瘤能力。在这里，我们概述了支持新概念免疫治疗动机的证据，即补充氧气（40-60%）或重新利用现有的氧合剂，与当前的免疫疗法联合使用。临床前研究为氧免疫治疗提供了强有力的支持，通过削弱 A2A 腺苷受体和 Hypoxia➔HIF-1α 轴的免疫抑制作用，使肿瘤更强烈地消退。这些研究的结果强调了全身氧合作为一种可行的、有前途的临床方法的价值，并且作为肿瘤生物学和癌症免疫学的机制研究的有价值的工具。在这一类新型抗肿瘤药物中，最有效和最可行的可能是氧合剂。
