Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, United States.
Center for Cancer Research, Purdue University, West Lafayette, IN, United States.
Front Immunol. 2018 Nov 8;9:2517. doi: 10.3389/fimmu.2018.02517. eCollection 2018.
Energy metabolism is key to the promotion of tumor growth, development, and metastasis. At the same time, cellular metabolism also mediates immune cell survival, proliferation and cytotoxic responses within the tumor microenvironment. The ability of natural killer cells to eradicate tumors relies on their ability to functionally persist for the duration of their anti-tumor effector activity. However, a tumor's altered metabolic requirements lead to compromised functional responses of cytokine-activated natural killer cells, which result in decreased effectiveness of adoptive cell-based immunotherapies. Tumors exert these immunosuppressive effects through a number of mechanisms, a key driver of which is hypoxia. Hypoxia also fuels the generation of adenosine from the cancer-associated ectoenzymes CD39 and CD73. Adenosine's immunosuppression manifests in decreased proliferation and impaired anti-tumor function, with adenosinergic signaling emerging as an immunometabolic checkpoint blockade target. Understanding such immunometabolic suppression is critical in directing the engineering of a new generation of natural killer cell-based immunotherapies that have the ability to more effectively target difficult-to-treat solid tumors.
能量代谢是促进肿瘤生长、发展和转移的关键。同时，细胞代谢也调节肿瘤微环境中免疫细胞的存活、增殖和细胞毒性反应。自然杀伤细胞消灭肿瘤的能力依赖于其在抗肿瘤效应活性持续期间发挥功能的能力。然而，肿瘤改变的代谢需求导致细胞因子激活的自然杀伤细胞的功能反应受损，从而降低了过继细胞免疫疗法的有效性。肿瘤通过多种机制发挥这种免疫抑制作用，其中一个关键驱动因素是缺氧。缺氧还促使来自癌症相关胞外酶 CD39 和 CD73 的腺苷生成。腺苷的免疫抑制表现在增殖减少和抗肿瘤功能受损，腺苷能信号转导作为免疫代谢检查点阻断的靶点出现。了解这种免疫代谢抑制对于指导新一代基于自然杀伤细胞的免疫疗法的工程设计至关重要，这些免疫疗法有能力更有效地靶向治疗困难的实体肿瘤。
