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.

中文翻译：

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肥胖对肿瘤进展过程中 T 细胞功能和 PD-1 检查点阻断的矛盾影响。

最近免疫疗法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。肥胖正在达到大流行的程度，并且是某些恶性肿瘤的主要危险因素，但肥胖对免疫反应的影响，一般来说以及在癌症免疫治疗中的影响，人们知之甚少。在这里，我们在多个物种和肿瘤模型中证明，肥胖会导致免疫老化、肿瘤进展和 PD-1 介导的 T 细胞功能障碍增加，这至少部分是由瘦素驱动的。然而，肥胖也与 PD-1/PD-L1 阻断对荷瘤小鼠和临床癌症患者的疗效增加有关。这些发现促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，并强调肥胖是某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反常影响。检查点封锁后免疫功能障碍和肿瘤进展加剧，但抗肿瘤功效和存活率也更高，检查点封锁直接针对肥胖中激活的一些途径。