Mechanistic Justifications of Systemic Therapeutic Oxygenation of Tumors to Weaken the Hypoxia Inducible Factor 1α-Mediated Immunosuppression
Mechanistic Justifications of Systemic Therapeutic Oxygenation of Tumors to Weaken the Hypoxia Inducible Factor 1α-Mediated Immunosuppression
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DOI：
10.1007/978-3-030-12734-3_8
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Sitkovsky, Michail
中科院分区：
文献类型：
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作者：
Hatfield, Stephen;Veszeleiova, Katarina;Sitkovsky, Michail
抗病原体和抗肿瘤免疫的长期研究为Hypoxia-HIF-1α的免疫抑制和免疫调节作用以及通过A2A腺苷受体信号通路（Hypoxia-A2A-腺苷能）介导的腺苷抑制作用提供了补充的遗传和药理学证据。当这条途径保护重要器官的发炎组织免受过度活跃的抗病原体免疫细胞的附带损害或使适应性免疫细胞分化时，它可以挽救生命。然而，缺氧-A2A-腺苷能免疫抑制也可以通过抑制T细胞和NK细胞的抗肿瘤作用来防止肿瘤排斥。此外，由于肿瘤细胞上缺氧-HIF-α介导的 MHC I 类分子丢失，这种抑制途径已被证明可以掩盖肿瘤。这表明，如果不同时使用抗缺氧-A2A-腺苷能药物来灭活缺氧和富含腺苷的肿瘤中的这种肿瘤保护机制，就不可能实现当前癌症免疫疗法的全部抗肿瘤能力。在这里，我们概述了呼吸补充氧气这一概念性新颖的免疫治疗动机的支持证据 (40-60%) 或重新利用现有的氧合剂与当前的免疫疗法相结合。临床前研究为氧免疫疗法提供了强有力的支持，通过削弱 A2A 腺苷受体和缺氧 -> HIF-1 α 轴的免疫抑制，使肿瘤消退更强烈。这些研究的结果强调了全身氧合在临床上可行、有前景的价值，以及作为肿瘤生物学和癌症免疫学机制研究的宝贵工具的价值。也许在这类新型抗肿瘤药物中最有效和可行的是氧合剂。
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-1 alpha 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-alpha-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-1 alpha 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.