The impact of obesity on radiotherapy anti-tumor effects

摘要 肥胖症在美国已经达到流行水平，并将很快超过吸烟成为第一大肥胖症 可预防癌症的原因。了解如何最好地治疗肥胖的癌症患者是一个关键的未得到满足的需求。 我们实验室的临床前数据显示，肥胖小鼠癌症模型对放射治疗(RT)的抵抗力增加。 临床数据显示，肥胖癌症患者对放射治疗的抵抗力更强，发病率更高。 复发的可能性。很少有机械论研究涉及这些发现并了解其机制。 控制肥胖患者的放射抵抗是一个知识空白。我们之前的研究表明，肥胖， 可能是通过瘦素，一种在肥胖中升高的荷尔蒙，可以改变癌症的增殖/存活，也可以改变 对癌症的免疫反应，导致癌症治疗效果的变化。肥胖症会抑制 适应性T细胞抗肿瘤免疫和免疫系统对RT的抗肿瘤作用有很强的贡献， 提供了一种潜在的机制，将肥胖和RT抵抗联系起来。肥胖相关脂肪因子可诱导抗肥胖 细胞凋亡因子与RT耐药。根据这些观察结果，我们假设肥胖会导致 直接通过增加癌细胞中的抗凋亡因子和间接通过诱导 抑制肿瘤微环境(TME)中的适应性抗肿瘤免疫。我们还假设 瘦素信号可能介导肥胖患者观察到的RT抵抗。这项提案旨在测试这些 假设，并进一步描绘肥胖和RT抵抗之间的机制联系，使用三个特定的目标。 我们将使用瘦肉和饮食诱导肥胖(DIO)小鼠模型，免疫抑制小鼠(Rag2-/-)，以及 缺乏功能性瘦素信号(db/db)或缺乏内源性瘦素(ob/ob)的小鼠 癌细胞内和肿瘤微环境内的瘦素信号影响对放射治疗的抵抗。 在特定的目标1中，我们将检查肥胖对RT疗效的影响，并检查其直接影响 对肿瘤的影响以及通过T细胞功能障碍或其他免疫机制的间接作用。以特定的目标 2我们将研究瘦素信号作为肥胖导致抵抗RT的潜在机制。 通过直接作用于癌细胞的增殖/存活，也通过间接作用于TME。在……里面 具体目标3我们将测试一个探索性假设，即消融性RT能够通过以下方式提高RT的疗效 克服肥胖诱导的直接(但与免疫无关)RT抵抗的机制。 了解肥胖如何影响RT反应并制定解决这些问题的策略将 改善接受RT治疗的肥胖症患者的预后。因此，这些研究可以产生重大的临床影响。 通过根据患者的新陈代谢量身定做RT治疗策略，代表着朝着个性化医学迈出的一步 参数。

Abstract Obesity has reached pandemic levels in the United States and will soon surpass smoking as the number one cause of preventable cancer. Understanding how to best treat obese cancer patients is a critical unmet need. Preclinical data from our lab show increased resistance to radiotherapy (RT) in obese mouse cancer models. Clinical data demonstrates that obese cancer patients are more resistant to radiotherapy and have higher rates of recurrence. Very few mechanistic studies have addressed these findings and understanding the mechanisms governing radiotherapy resistance in obesity is a gap in knowledge. Our prior studies demonstrate that obesity, likely via leptin, a hormone elevated in obesity, can alter the proliferation / survival of cancers and also change the immune response to cancer, leading to changes in the efficacy of cancer therapies. Obesity suppresses adaptive T cell anti-tumor immunity and the immune system strongly contributes to the anti-tumor effects of RT, providing a potential mechanism linking obesity and RT resistance. Obesity related adipokines can induce anti- apoptotic factors and RT resistance. Based on these observations we hypothesize that obesity induces resistance to RT directly by increasing anti-apoptotic factors in cancer cells and indirectly by inducing suppression of adaptive anti-tumor immunity in the tumor microenvironment (TME). We also hypothesize that leptin signaling may mediate the RT resistance observed in obesity. This proposal seeks to test these hypotheses and further delineate mechanistic links between obesity and RT resistance using three specific aims. We will use lean and diet induced obesity (DIO) mouse models, immunosuppressed mice (Rag2 -/-), as well as mice that lack functional leptin signaling (db/db) or lack endogenous leptin (ob/ob) to evaluate how obesity and leptin signaling within cancer cells and within the tumor microenvironment influence resistance to radiotherapy. In specific aim 1 we will examine the effects of obesity on the efficacy of RT and also examine the direct effects on the tumor as well as the indirect effects via T cell dysfunction or other immune mechanisms. In specific aim 2 we will investigate leptin signaling as an underlying mechanism whereby obesity induces resistance to RT both through direct effects on cancer cell proliferation / survival and also through indirect effects on the TME. In specific aim 3 we will test an exploratory hypothesis that ablative RT is able to improve RT efficacy in obesity by overcoming the mechanisms of obesity induced direct (but not immune related indirect) RT resistance. Understanding how obesity impacts RT response and developing strategies to address these issues will improve outcomes in obese patients treated with RT. Thus, these studies can have a major clinical impact and represent a step towards personalized medicine by tailoring RT treatment strategies to a patient's metabolic parameters.