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：
10570962
负责人：
Susan M Kaech
金额：
$ 58.73万
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/10570962
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 Lymphocytic Infiltrate MHC antigen Malignant Neoplasms Metabolic Metabolic Control Metabolic Pathway Metabolism Modeling Nature Nutrient Nutrient availability Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phenotype Production Proliferating Prostaglandin D2 Proteins Resistance Resources Seminal Signal Transduction Source Stress T cell infiltration T cell response T-Lymphocyte Testing Therapeutic Time Tumor Immunity Tumor-Derived Tumor-Infiltrating Lymphocytes Up-Regulation War Work aerobic glycolysis anti-tumor immune response cancer cell cancer immunotherapy cancer infiltrating T cells cancer therapy cell growth combat cost eicosanoid metabolism exhaust exhaustion flexibility immune cell infiltrate 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 programs response stem trait tumor tumor immunology tumor metabolism tumor microenvironment tumor progression 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.

项目摘要：代谢转化是癌细胞的标志性特征，允许持续的合成代谢代谢燃料电池的生长和增殖，当蒸馏到其核心时，癌症最终是一种不受限制的疾病合成代谢。然而，尚不清楚肿瘤细胞的异常代谢活性如何影响肿瘤微环境中相邻免疫细胞的功能，表型和代谢状态。这开发新的免疫疗法，这些免疫疗法刺激对对照或放射性癌症的抗肿瘤T细胞反应是癌症治疗的革命性和有望的领域，但肿瘤的免疫抑制性质微环境仍然是增加对患者的频率的最大障碍免疫疗法。我们建议一个主要组成部分决定肿瘤微环境（TME）是否为免疫支持或免疫抑制是肿瘤细胞的代谢状态。该模型基于事实像肿瘤细胞一样，肿瘤浸润淋巴细胞（TIL）也需要高氧糖酵解和谷氨酰胺分解以增殖并执行结核效应子功能。有充分记录的CD8+ T细胞在肿瘤中受到功能抑制或“疲惫”，也许是这种抑制的主要来源由代谢活性肿瘤与免疫细胞之间的竞争引起的营养剥夺相同的营养。肿瘤和免疫细胞之间的“代谢拔河”模型，例如葡萄糖和谷氨酰胺对如何形成免疫抑制性TME的观点完全不同。为了弥合癌症免疫学上的这一差距，我们将确定代谢途径，尤其是那些途径参与脂质稳态，由黑色素瘤和胰腺导管腺癌（PDAC）使用浸润的免疫电池的质量和功能。具体来说，在AIM 1中，我们将研究肿瘤细胞中的脂肪生成和脂解确定这如何影响脂质和脂蛋白在 TME和TIL的类型。我们将测试CD8+ TILS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AIM 2中，我们将调查是否tils 通过上调转运蛋白CD36，对TME中的高脂血症和OX-LDL做出反应，并阐明了如何 OX-LDL-CD36信号传导抑制CD8+ TIL效应子功能（这项工作是第一次探索此途径据我们所知，CD8+ T细胞）。最后，我们发现花生四烯酸（AA）代谢与TIL浸润有关在AIM 3中，我们将探索一个新模型，即随肿瘤的进展，PGD2和PGE2的平衡发生了变化，将免疫支持TME转换为更具免疫抑制的TME。在所有三个目标中，我们都将针对这些代谢途径可以发现新颖的疗法组合，以提高当前临床用途的免疫疗法。这项工作有很大的潜力可以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组织化学的干预措施。