Understanding how metabolic heterogeneity in cancer affects the tumor microenvironment and anti-tumor immunity

项目摘要： 代谢转化是癌细胞的标志性特征，其允许持续的合成代谢， 燃料电池的生长和增殖，当蒸馏到其核心，癌症最终是一种疾病， 合成代谢然而，肿瘤细胞的异常代谢活性如何影响肿瘤细胞的生长， 肿瘤微环境中邻近免疫细胞的功能、表型和代谢状态。的 开发刺激抗肿瘤T细胞应答以控制或根除癌症的新免疫疗法 是癌症治疗的一个革命性和有前途的领域，但肿瘤的免疫抑制性质， 微环境仍然是增加患者响应频率的最大障碍。 免疫疗法我们提出，决定肿瘤微环境（TME）是否 免疫支持或免疫抑制是肿瘤细胞的代谢状态。这个模型是基于 与肿瘤细胞一样，肿瘤浸润淋巴细胞（TIL）也需要高速率的有氧糖酵解， 去甲肾上腺素分解以增殖和执行杀肿瘤效应器功能。有充分的证据表明，CD 8 + T细胞 在肿瘤中被功能性抑制或“耗尽”，这种抑制的主要来源可能仅仅是 营养缺乏源于代谢活性肿瘤和免疫细胞之间的竞争， 同样的营养。这种肿瘤和免疫细胞之间的“代谢拔河”模型， 葡萄糖和谷氨酰胺对如何形成免疫抑制性TME提出了完全不同的观点。 为了弥合癌症免疫学的这一差距，我们将确定代谢途径，特别是那些 参与脂质体内平衡，被黑色素瘤和胰腺导管腺癌（PDAC）利用， 浸润免疫细胞的质量和功能。具体而言，在目标1中，我们将研究以下方面的平衡： 肿瘤细胞中的脂肪生成和脂肪分解，以确定这如何影响肿瘤细胞中脂质和脂蛋白的组成。 TME和存在的TIL的类型。我们将测试CD 8 + TIL是否代谢适应肿瘤细胞的变化， 代谢，并了解这如何影响他们的抗肿瘤免疫反应。在目标2中，我们将研究TILs是否 通过上调转运蛋白CD 36对TME中的高脂血症和Ox-LDL作出反应，并阐明 Ox-LDL-CD 36信号转导抑制CD 8 + TIL效应子功能（这项工作是第一次在细胞内探索这一途径。 CD 8 + T细胞）。最后，我们发现花生四烯酸（AA）代谢与TIL浸润相关 在目标3中，我们将探索一种新的模型，即随着肿瘤的进展，PGD 2和PGE 2的平衡发生变化， 将免疫支持性TME转化为更具免疫抑制性的TME。在这三个目标中，我们将针对 这些代谢途径，以发现新的治疗组合，提高疗效， 免疫疗法目前在临床上使用。这项工作有很大的潜力，揭示几个新的层面 肿瘤微环境中的免疫抑制和刺激抗肿瘤免疫的干预措施。

Project Summary: Metabolic transformation is a hallmark feature of cancer cells that allows sustained anabolic metabolism to fuel cell growth and proliferation, and when distilled to its core, cancer is ultimately a disease of unchecked anabolic metabolism. Yet, it is not well understood how the aberrant metabolic activity of tumor cells affects the function, phenotype and metabolic states of neighboring immune cells in the tumor microenvironment. The development of new immunotherapies that stimulate anti-tumor T cell responses to control or eradicate cancer is a revolutionary and promising area of cancer therapy, but the immunosuppressive nature of the tumor microenvironment remains the biggest obstacle to increasing the frequency of patients that respond to immunotherapy. We propose that a major component dictating whether the tumor microenvironment (TME) is immuno-supportive or immuno-suppressive is the metabolic state of tumor cells. This model is based on the fact that, like tumor cells, tumor infiltrating lymphocytes (TILs) also require high rates of aerobic glycolysis and glutaminolysis to proliferate and perform tumoricidal effector functions. It is well documented that CD8+ T cells are functionally suppressed or “exhausted” in tumors and perhaps a primary source of this suppression is simply nutrient deprivation stemming from competition between metabolically active tumor and immune cells for the same nutrients. This model of a “metabolic tug-of-war” between tumor and immune cells over nutrients such as glucose and glutamine presents an entirely different perspective on how an immunosuppressive TME may form. To bridge this gap in cancer immunology, we will determine how metabolic pathways, particularly those involved in lipid homeostasis, utilized by melanoma and pancreatic ductal adenocarcinoma (PDAC) affect the quality and function of infiltrating immune cells. Specifically, in Aim 1 we will investigate the balance between lipogenesis and lipolysis in tumor cells to determine how this affects the composition of lipids and lipoproteins in the TME and the types of TILs present. We will test if CD8+ TILs metabolically adapt to changes in tumor cell metabolism and learn how this affects their anti-tumor immune response. In Aim 2, we will investigate if TILs respond to hyperlipidemia and Ox-LDL in the TME via upregulation of the transporter CD36 and elucidate how Ox-LDL-CD36 signaling suppresses CD8+ TIL effector functions (this work is the first to explore this pathway in CD8+ T cells to our knowledge). Lastly, we found arachidonic acid (AA) metabolism correlates with TIL infiltration and in Aim 3 we will explore a new model that the balance of PGD2 and PGE2 changes as tumors progress, converting an immuno-supportive TME to one that is more immuno-suppressive. In all three Aims we will target these metabolic pathways to discover novel combinations of therapies that enhance the efficacy of immunotherapies currently in clinical use today. This work has great potential to uncover several new dimensions of immunosuppression in the tumor microenvironment and interventions to stimulate anti-tumor immunity.