Halpin-Veszeleiova Katarina, Mallouh Michael P, Williamson Lucy M, Apro Ashley C, Botticello-Romero Nuria R, Bahr Camille, Shin Maureen, Ward Kelly M, Rosenberg Laura, Ritov Vladimir B, Sitkovsky Michail V, Jackson Edwin K, Spiess Bruce D, Hatfield Stephen M
Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.
Department of Surgery, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
JCI Insight. 2025 Mar 24;10(6):e174675. doi: 10.1172/jci.insight.174675.
Hypoxia/hypoxia-inducible factor 1α-driven immunosuppressive transcription and cAMP-elevating signaling through A2A adenosine receptors (A2ARs) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patients refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). We show that oxygenation agent therapy (a) eliminates tumor hypoxia, (b) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby (c) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to reprogramming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immunosuppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy.
缺氧/缺氧诱导因子1α驱动的免疫抑制转录以及通过A2A腺苷受体（A2ARs）的环磷酸腺苷升高信号通路代表了一条主要的肿瘤保护途径，可实现免疫逃逸。最近，对于所有其他疗法均无效的患者，通过阻断腺苷生成酶CD73和A2AR取得了有前景的临床结果，这证实了靶向缺氧-腺苷能信号传导的重要性。我们报告了一种可行的方法，即使用载氧纳米乳剂（全氟化碳血液替代品）靶向缺氧-腺苷能免疫抑制的上游阶段。我们表明，氧合剂疗法（a）消除肿瘤缺氧，（b）提高内源性产生和过继转移的T细胞的疗效，从而（c）促进不同解剖部位肿瘤的消退。我们表明，T细胞和NK细胞都会避开缺氧的肿瘤区域，并且氧合剂疗法逆转缺氧会由于肿瘤微环境（TME）的重编程而增加肿瘤内活化T细胞和NK细胞的浸润。因此，重新利用氧合剂并结合补充氧气可能通过防止缺氧-腺苷能抑制、促进免疫细胞浸润和增强效应反应来改善当前的癌症免疫疗法。这些数据还表明，在用氧合剂疗法预处理患者后，可能会在过继细胞疗法或其他形式的免疫疗法之前将TME从免疫抑制状态重编程为免疫许可状态。
