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

了解癌症中的代谢异质性如何影响肿瘤微环境和抗肿瘤免疫

基本信息

批准号：
9981453
负责人：
Susan M Kaech
金额：
$ 59.93万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9981453
关键词：
Address Adopted Affect Antigen Presentation Arachidonic Acids Area CD36 gene CD8-Positive T-Lymphocytes CD8B1 gene Cancer Biology Cell Proliferation Cell Survival Cell physiology Cells Characteristics Clinical Combined Modality Therapy Complement Development Dimensions Dinoprostone Disease Environment Equilibrium Fatty Acids Frequencies Functional disorder Glucose Glutamine Goals Heterogeneity Homeostasis Hyperlipidemia Hypoxia Immune Immunity Immunologic Surveillance Immunosuppression Immunotherapy Impairment Infiltration Influentials Intervention Learning Lipids Lipolysis Lipoproteins Lymphocyte Function MHC antigen Malignant Neoplasms Metabolic Metabolic Control Metabolic Pathway Metabolism Modeling Nature Nutrient Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phenotype Production Proliferating Prostaglandin D2 Proteins Resistance Resources Seminal Signal Transduction Source Stress T cell response T-Lymphocyte Testing Therapeutic Time Tumor Immunity Tumor-Derived Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Up-Regulation War Work aerobic glycolysis anti-tumor immune response base cancer cell cancer immunotherapy cancer therapy cell growth combat cost eicosanoid metabolism exhaust exhaustion flexibility immune checkpoint immunogenicity immunoregulation improved lipid biosynthesis melanoma neoplastic cell novel nutrient deprivation oxidized low density lipoprotein programmed cell death ligand 1 programmed cell death protein 1 response stem trait tumor tumor immunology tumor metabolism tumor microenvironment tumor-immune system interactions

项目摘要

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.

项目概要：代谢转化是癌细胞的一个标志特征，它允许持续的合成代谢代谢燃料电池的生长和增殖，当深入探讨其核心时，癌症最终是一种不受控制的疾病然而，目前尚不清楚肿瘤细胞的异常代谢活动如何影响合成代谢。肿瘤微环境中邻近免疫细胞的功能、表型和代谢状态。开发新的免疫疗法，刺激抗肿瘤 T 细胞反应以控制或根除癌症是癌症治疗的一个革命性的、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我们提出决定肿瘤微环境（TME）是否是免疫疗法的一个主要因素。免疫支持或免疫抑制是肿瘤细胞的代谢状态，这一模型是基于这样的事实。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和 CD8+ T 细胞通过谷氨酰胺分解来增殖并发挥杀肿瘤效应功能。在肿瘤中受到功能性抑制或“耗尽”，也许这种抑制的主要来源只是由于代谢活跃的肿瘤和免疫细胞之间的竞争而导致营养缺乏肿瘤和免疫细胞之间对营养物质（例如，）的“代谢拉锯战”模型。葡萄糖和谷氨酰胺对免疫抑制性 TME 的形成方式提出了完全不同的观点。为了弥补癌症免疫学方面的这一差距，我们将确定代谢途径，特别是那些参与脂质稳态，被黑色素瘤和胰腺导管腺癌 (PDAC) 利用，影响具体来说，在目标 1 中，我们将研究浸润免疫细胞的质量和功能之间的平衡。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我们将测试 CD8+ TIL 是否在代谢上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 TIL 是否存在。通过上调转运蛋白 CD36 来应对 TME 中的高脂血症和 Ox-LDL，并阐明如何 Ox-LDL-CD36 信号传导抑制 CD8+ TIL 效应器功能（这项工作是第一个在据我们所知，CD8+ T 细胞）最后，我们发现花生四烯酸 (AA) 代谢与 TIL 浸润相关。在目标3中，我们将探索一种新模型，即PGD2和PGE2的平衡随着肿瘤的进展而变化，将免疫支持性 TME 转变为免疫抑制性更强的 TME 在所有三个目标中，我们都将瞄准这一目标。这些代谢途径来发现新的疗法组合，以增强疗效目前临床上使用的免疫疗法具有揭示几个新维度的巨大潜力。肿瘤微环境中的免疫抑制和刺激抗肿瘤免疫的干预措施。