Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade
Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade
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DOI：
10.1038/s41591-018-0221-5
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发表时间：
2019-01-01
期刊：
影响因子：
82.9
通讯作者：
Monjazeb, Arta M.
中科院分区：
文献类型：
--
作者：
Wang, Ziming;Aguilar, Ethan G.;Monjazeb, Arta M.
免疫疗法最近的成功改变了癌症治疗的范式，但由于只有一部分患者对免疫疗法有反应，因此必须确定影响结果的因素。肥胖已达到流行病的程度，并且是某些恶性肿瘤的主要危险因素，但肥胖对一般免疫反应和癌症免疫治疗的影响却知之甚少。在这里，我们在多个物种和肿瘤模型中证明，肥胖会导致免疫衰老、肿瘤进展和 PD-1 介导的 T 细胞功能障碍的增加，而这种功能障碍至少部分是由瘦素驱动的。然而，肥胖也与荷瘤小鼠和临床癌症患者中 PD-1/PD-L1 阻断的功效增强相关。这些发现增进了我们对肥胖引起的免疫功能障碍及其在癌症中的后果的理解，并强调肥胖作为一些癌症免疫疗法的生物标志物。这些数据表明肥胖对癌症的影响是矛盾的。直接针对肥胖中激活的一些途径的检查点阻断后，免疫功能障碍和肿瘤进展加剧，但抗肿瘤功效和生存率也更高。
The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.