Overcoming obesity-associated immunotherapy resistance in renal cancer

摘要：我们对宿主免疫系统用来对抗生长肿瘤的机制的理解 近几十年来呈指数级增长，带来了新的治疗方法的发展 例如免疫检查点阻断(ICB)，它使癌症治疗发生了革命性变化。尽管如此 随着免疫技术的进步，许多患者甚至对最有希望的免疫疗法也没有反应。因此，存在一个持久的 迫切需要找出导致这些原本有效的药物疗效有限的宿主因素 癌症患者的免疫疗法。毫不奇怪，识别免疫疗法耐药的机制是 一个活跃的研究领域。然而，这一领域的绝大多数临床前和临床研究并不是 考虑到肥胖等常见患者并存疾病的影响。这一点值得注意，因为它是 据估计，到2050年，美国一半的成年人将患有肥胖(定义为身体质量指数(BMI)) 30公斤/平方米)。研究集中在了解肥胖对抗肿瘤免疫和癌症的影响 免疫治疗的结果在数量上急剧增长。然而，该领域仍然缺乏一个明确的 了解肥胖何时对癌症患者有益，何时不有益，以及为什么。肾癌是 肥胖会增加患病率的13种肿瘤类型之一。多项独立研究发现， 即使在晚期肾癌患者中，50-60%的患者在ICB治疗时也会出现BMI定义的超重或肥胖 入会仪式。因此，确定与肥胖相关的ICB抵抗与易感性的生物驱动因素 肾癌是一个至关重要的研究领域，它可能会直接影响大多数与 这种病。我们一直在宿主肥胖的背景下研究ICB抵抗。我们回顾了 检查了接受标准抗PD-1治疗的肾癌患者队列的结果。在病人中 在治疗开始时有BMI定义的肥胖，67%的人在12个月时出现癌症进展，而 剩下的33%是无进展的，说明宿主肥胖对患者的影响是高度可变的 结果。这一趋势反映在我们的原位肾癌临床前模型中，在该模型中，我们发现 在接受了基于PD-1的抗PD-1联合疗法的小鼠中，宿主肥胖与癌症进展有关 免疫疗法。在这里，我们将结合临床前的小鼠和预期的人类受试者研究来测试 假设ICB治疗期间持续高水平的IL-1b炎症与不良相关 肥胖的肾癌患者的预后。我们进一步预测，阻断肿瘤内IL-1b将 导致良好的肾脏TME重塑，并改善ICB结果。我们的发现将允许 对肾癌ICB抵抗的肥胖相关介质的更细微的理解 患者，从而：1)提供新的指标，用于识别对ICB反应较小的患者 以及2)促进开发新的治疗和临床管理策略 用ICB疗法治疗的肾细胞癌或其他实体肿瘤。

SUMMARY: Our understanding of the mechanisms used by the host immune system to fight growing tumors has increased exponentially in recent decades, ushering in the development of new therapeutic approaches such as immune checkpoint blockade (ICB) that have revolutionized cancer treatment. Despite these advances, many patients fail to respond to even the most promising immunotherapies. Thus, there persists an urgent need to identify the host factors responsible for the limited efficacy of these otherwise potent immunotherapies in cancer patients. Not surprisingly, identifying mechanisms of immunotherapy resistance is an active area of research. However, the vast majority of pre-clinical and clinical studies in this area do not take into account the effects of common patient co-morbidities like obesity. This is notable because it is estimated that by 2050 half of all adults in the U.S. will have obesity (defined as a Body Mass Index (BMI) of >30 kg/m2). Studies focused on understanding the impact of obesity on anti-tumor immunity and cancer immunotherapy outcomes have grown dramatically in number. However, the field still lacks a clear understanding of when obesity is beneficial for cancer patients, when it is not, and why. Renal cancer is one of 13 tumor types whose prevalence is increased by obesity. Multiple independent studies have found that even in advanced renal cancer patients, 50-60% display BMI-defined overweight or obesity at ICB treatment initiation. Thus, identifying the biological drivers of obesity-associated ICB resistance versus susceptibility in renal cancer is a critically important area of research that could directly impact the majority of patients battling this disease. We have been studying ICB resistance in the context of host obesity. We retrospectively examined outcomes in a cohort of renal cancer patients who received standard of care anti-PD-1. In patients with BMI-defined obesity at treatment initiation, 67% exhibited cancer progression at 12 months, whereas the remaining 33% were progression-free, illustrating the highly variable effects of host obesity on patient outcomes. This trend was reflected in our pre-clinical model of orthotopic renal cancer, in which we found that host obesity is linked to cancer progression in 56% of mice that received an anti-PD-1-based combinatorial immunotherapy. Here we will combine pre-clinical murine and prospective human subject studies to test the hypothesis that sustained high levels of IL-1b inflammation during ICB therapy are associated with poor outcomes in renal cancer patients who have obesity. We further predict that blockade of intratumoral IL-1b will result in a favorable remodeling of the renal TME and improve ICB outcomes. Our findings will permit a more nuanced understanding of the obesity-associated mediators of ICB resistance in renal cancer patients, thereby: 1) providing new metrics to use for identifying patients who are less likely to respond to ICB and 2) facilitating the development of new therapeutic and clinical management strategies for patients with RCC or other solid tumors that are treated with ICB therapeutics.