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

项目总结： 代谢转化是癌细胞的一个显著特征，它允许持续的合成代谢 燃料电池的生长和增殖，当蒸馏到它的核心时，癌症最终是一种肆无忌惮的疾病 合成代谢。然而，目前还不清楚肿瘤细胞的异常代谢活动是如何影响 肿瘤微环境中邻近免疫细胞的功能、表型和代谢状态。这个 刺激抗肿瘤T细胞反应以控制或根除癌症的新免疫疗法的发展 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反应频率的最大障碍 免疫疗法。我们认为，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。这个模型是基于这样一个事实 和肿瘤细胞一样，肿瘤浸润性淋巴细胞(TIL)也需要很高的有氧糖酵解和 谷氨酰胺分解以增殖和执行杀瘤效应功能。CD8 T细胞已经得到了很好的证明 在肿瘤中被功能抑制或“耗尽”，也许这种抑制的一个主要来源只是 由于代谢活跃的肿瘤和免疫细胞之间竞争而导致的营养缺乏 同样的营养成分。这种肿瘤和免疫细胞之间围绕营养物质的“代谢拉锯战”模型 葡萄糖和谷氨酰胺对免疫抑制的TME如何形成提出了完全不同的观点。 为了弥合癌症免疫学中的这一差距，我们将确定代谢途径，特别是那些 参与脂类稳态，被黑色素瘤和胰腺导管腺癌(PDAC)所利用，影响 浸润性免疫细胞的性质和功能。具体地说，在目标1中，我们将调查两者之间的平衡 肿瘤细胞的脂肪生成和脂解作用，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类型。我们将测试CD8 TIL在代谢上是否适应肿瘤细胞的变化 并了解这如何影响它们的抗肿瘤免疫反应。在目标2中，我们将调查TIL是否 通过上调转运体CD36对TME中高脂血症和氧化低密度脂蛋白的反应并阐明如何 OX-LDL-CD36信号抑制CD8 TIL效应功能(这项工作是首次探索这一途径)。 据我们所知，CD8 T细胞)。最后，我们发现花生四烯酸(AA)代谢与TIL的渗透有关。 在目标3中，我们将探索一种新的模型，即PGD2和PGE2的平衡随着肿瘤的进展而变化， 将免疫支持的TME转变为免疫抑制更强的TME。在所有这三个目标中，我们都将 这些代谢途径可以发现新的治疗组合，从而提高患者的疗效 目前临床上使用的免疫疗法。这项工作有很大的潜力揭示几个新的维度 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.