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：
10378495
负责人：
Bradley Reinfeld
金额：
$ 4.95万
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/10378495
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 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.

项目概要细胞能量失调和避免免疫破坏被认为是癌症的标志。刺激抗肿瘤免疫力现在是癌症治疗的主要目标免疫检查点的成功。阻断（ICB）疗法展示了这种范例的巨大前景，但仍然只有少数患者对这种治疗方式有持久的反应，我建议改变体内的代谢程序。通过揭示这些，肿瘤微环境（TME）可能与功能失调的抗肿瘤免疫反应有关。相互作用，可能存在提高免疫疗法疗效的新机会。数据表明，肿瘤模型中的骨髓细胞在 TME 中摄取显着更多的葡萄糖，而转化细胞似乎消耗谷氨酰胺，肾细胞癌（RCC）的代谢发生改变。我们已经充分确定了肿瘤的特点是复杂且丰富的免疫细胞浸润。小组和其他人认为这些肿瘤浸润 T 细胞代谢受损，抗肿瘤作用有限尽管 ICB 改善了 RCC 患者的生存率，但只有少数患者具有完全的生存能力。 RCC 的独特遗传学可能有助于这些 T 细胞刺激剂的反应。讨论了透明细胞肾细胞癌中的抑制性 TME，即肿瘤抑制因子 von Hippel Lindau (VHL) 的丧失。此外，在侵袭性 II 型乳头状 RCC 中，缺失是肿瘤发生的必要事件。富马酸水合酶（FH）的缺失或三羧酸循环中的其他缺陷是肿瘤形成所必需的。遗传事件是由我的导师 WK Rathmell 和其他人定义的，这些遗传事件贯穿 RCC 结果。致癌转录因子 (TF) 缺氧诱导因子 1 和 2 的积累。随着这些 TF 的积累，RCC 肿瘤细胞通过减少对能量的依赖来改变其能量需求三羧酸循环和线粒体呼吸，同时增加细胞糖酵解，因此，RCC 是。独特地进一步研究肿瘤细胞代谢对淋巴和骨髓细胞命运的影响，该项目将应用新型免疫活性、非免疫原性 CRISPR/Cas9 模型来研究其功能。 RCC 遗传事件（VHL 和 FH 丢失）对免疫浸润和激活的影响。还将检查抑制免疫细胞葡萄糖和谷氨酰胺摄取的不同结果 TME 中的适应性和功能这项工作将得到体外初级研究的补充。人类 RCC 类器官模型，用于检查遗传和化学扰动对人类的影响这项研究将最终揭示肿瘤的异型本质。通过了解异质 TME 中关键细胞类型的不同代谢能力，这项工作将提高我们支持浸润免疫细胞的抗肿瘤能力的能力。数据将有助于未来的药理学策略，从而提高我们诱导具有临床意义的能力较大群体患者的抗肿瘤免疫反应。