Metabolic Contributions of Individual Cellular Compartments to the Diversity of the Tumor Microenvironment in Renal Cell Carcinoma

肾细胞癌中各个细胞区室的代谢对肿瘤微环境多样性的贡献

基本信息

批准号：
10155823
负责人：
Bradley Reinfeld
金额：
$ 3.08万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155823
关键词：
Amino Acids Anabolism Area Award Biological Models Biomass CRISPR/Cas technology Cancer Biology Cancer Model Cells Cellular Metabolic Process Chemical Structure Chemicals Citric Acid Cycle Clear Cell Clear cell renal cell carcinoma Complement Complex Consumption Data Defect Development Disease Endothelium Epithelial Erythrocytes Event Foundations Fractionation Fumarate Hydratase Future Genes Genetic Genetically Engineered Mouse Glucose Glutamine Glycolysis Goals Grant Human Hypoxia Inducible Factor Immune Immune mediated destruction Immune response Immunocompetent Immunology Immunophenotyping Immunotherapy Impairment Implant In Vitro In complete remission Individual Infiltration Investigation Light Link Lymphoid Cell Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Measures Mentors Metabolic Metabolic Pathway Metabolism Minority Mitochondria Modality Modeling Mutation Myeloid Cells Nature Nutrient Oncogenic Organoids Outcome Papillary Pathogenesis Pathway interactions Patient Care Patients Pharmacology Phenotype Physicians Positron-Emission Tomography Proliferating Renal Cell Carcinoma Resources Respiration Role Science Scientist Seminal Signal Transduction T-Lymphocyte Techniques Tracer Tumor Biology Tumor Immunity Tumor Suppressor Proteins Tumor-infiltrating immune cells Work anti-tumor immune response base cancer cell cancer therapy cell transformation cell type chemokine clinically significant cohort combinatorial fitness glucose uptake human disease human model hypoxia inducible factor 1 immune activation immune checkpoint blockade improved inhibitor/antagonist kidney cell macrophage mouse model neoplastic cell novel pre-clinical research programs response skills small molecule inhibitor success targeted agent therapeutically effective tool transcription factor tumor tumor growth tumor metabolism tumor microenvironment tumor-immune system interactions tumorigenesis uptake

项目摘要

PROJECT SUMMARY Deregulating cellular energetics and avoiding immune destruction are considered hallmarks of cancer. Stimulating anti-tumor immunity is now a chief goal of cancer therapy. The success of immune checkpoint blockade (ICB) therapy demonstrates the tremendous promise of this paradigm, but still only a minority of patients have durable responses with this modality of therapy. I propose that altered metabolic programs in the tumor microenvironment (TME) may be linked to dysfunctional anti-tumor immune responses. By revealing these interactions, there may be new opportunities to improve the efficacy of immunotherapy. I have generated novel data demonstrating that myeloid cells across tumor models uptake significantly more glucose in the TME, while transformed cells appear to be glutamine consuming. Renal Cell Carcinomas (RCC) are metabolically altered tumors that are characterized by a complex and abundant immune cell infiltrate. It is well established by our group and others that these tumor-infiltrating T cells are metabolically compromised and have limited antitumor capacity. Even though ICB has improved RCC patient survival, only a minority of patients have complete responses with these T cell stimulating agents. The unique genetics of RCC may contribute to this aforementioned suppressive TME. In clear cell RCCs, the loss of the tumor suppressor von Hippel Lindau (VHL) is a necessary event for tumorigenesis. Additionally, in a subset of aggressive Type II papillary RCCs, the loss of fumarate hydratase (FH) or other defects in the tricarboxylic acid cycle are required for tumor formation. These genetic events were defined by my mentor WK Rathmell and others. These genetic events across RCC results in accumulation of the oncogenic transcription factors (TFs) hypoxia inducible factor 1 and 2. With accumulation of these TFs, RCC tumor cells shift their energetic requirements by decreasing their reliance on the tricarboxylic acid cycle and mitochondrial respiration while increasing cellular glycolysis. Therefore, RCC is uniquely posed to further study the impact of tumor cell metabolism on lymphoid and myeloid cell fate and function. This project will apply novel immunocompetent, non-immunogenic CRISPR/Cas9 models to study the effect of RCC genetic events (VHL and FH loss) on immune infiltration and activation. In these models, I will also examine the differential outcomes of inhibiting glucose and glutamine uptake on immune cell fitness and function in the TME. This work will be complemented by studies that employ in vitro primary human RCC organoid models to examine the impact of genetic and chemical perturbations on human tumor resident immune cell metabolism. This study will ultimately shed light on the heterotypic nature of tumor metabolism. By understanding the divergent metabolic capacities of the key cell types in the heterogenous TME, this work will increase our capability to support anti-tumor capacity of infiltrating immune cells. These data will aid future pharmacological strategies that can increase our ability to induce clinically significant anti-tumor immune responses in larger cohorts of patients.

项目摘要过度调节细胞能量和避免免疫损害被认为是癌症的标志。刺激抗肿瘤免疫组织化学现在是癌症治疗的主要目标。免疫切除点的成功胃（ICB）疗法证明了这种范式的巨大希望，但仍然只有少数患者对这种治疗方式具有持久的反应。我建议改变代谢程序肿瘤微环境（TME）可能与功能障碍的抗肿瘤免疫反应有关。通过揭示这些相互作用，可能会有新的机会提高免疫疗法的效率。我创造了小说数据表明，跨肿瘤模型摄取的髓样细胞在TME中的葡萄糖明显更大，而转化的细胞似乎是谷氨酰胺消耗的。肾细胞癌（RCC）代谢改变以复杂而丰富的免疫细胞浸润为特征的肿瘤。它是我们的组和其他表明这些肿瘤浸润的T细胞被代谢损害，抗肿瘤有限容量。即使ICB改善了RCC患者的生存，但只有少数患者才能完成这些T细胞刺激剂的反应。 RCC的独特遗传学可能有助于此关于抑制性TME。在透明细胞RCC中，肿瘤抑制剂von Hippel lindau（VHL）的丧失是肿瘤发生的必要事件。此外，在侵略性II型乳头状RCC的子集中，损失肿瘤形成需要富马酸水平酶（FH）或三核酸周期中的其他缺陷。这些遗传事件由我的导师WK Rathmell等定义。跨RCC结果的这些遗传事件在致癌转录因子（TFS）缺氧诱导因子1和2的积累中。和这些TF的积累，RCC肿瘤细胞通过减少其退休而改变其能量需求三核酸周期和线粒体呼吸，同时增加细胞糖酵解。因此，RCC是独特地提出了进一步研究肿瘤细胞代谢对淋巴样和髓样细胞命运的影响功能。该项目将采用新颖的免疫能力，非免疫原性CRISPR/CAS9模型来研究 RCC遗传事件（VHL和FH损失）对免疫浸润和激活的影响。在这些模型中，我还将检查抑制谷氨酸和谷氨酰胺在免疫细胞上的差异结果 TME中的适应性和功能。这项工作将由员工在体外初级的研究完成人类RCC器官模型检查遗传和化学扰动对人的影响肿瘤居民免疫细胞代谢。这项研究最终将阐明肿瘤的异型性质代谢。通过了解键细胞类型在异源TME中的不同代谢能力，这项工作将提高我们支持浸润免疫力抗肿瘤能力的能力。这些数据将有助于未来的药理学策略，以提高我们诱导临床意义的能力较大的患者同类群中的抗肿瘤免疫复杂。