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

• 批准号: 10607997
• 负责人: Bradley Reinfeld
• 金额: $ 2.64万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607997
• 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; Dendritic Cells; Development; Disease; Disease remission; Endothelial Cells; Epithelium; Erythrocytes; Event; 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; Inflammatory; Investigation; Link; Lymphoid Cell; Macrophage; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mentors; Metabolic; Metabolic Pathway; Metabolism; Minority; Mitochondria; Modality; Modeling; Mutation; Myeloid Cells; Natural Killer Cells; Nature; Nutrient; Oncogenic; Organoids; Outcome; Papillary; Pathogenesis; Pathway interactions; Patient Care; Patients; Phenotype; Physicians; Positron-Emission Tomography; Proliferating; Renal Cell Carcinoma; Resources; Respiration; Role; Science; Scientist; Seminal; Signal Transduction; Starvation; T-Lymphocyte; Techniques; Tracer; Tumor Biology; Tumor Immunity; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Warburg Effect; Work; anti-tumor immune response; cancer cell; cancer infiltrating T cells; cancer therapy; cell transformation; cell type; chemokine; clinically significant; cohort; combinatorial; fitness; glucose uptake; human disease; human model; immune activation; immune cell infiltrate; immune checkpoint blockade; improved; inhibitor; kidney cell; mouse model; neoplastic cell; novel; pharmacologic; 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

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 细胞能量失调和避免免疫破坏被认为是癌症的标志。 刺激抗肿瘤免疫现在是癌症治疗的主要目标。免疫检查点的成功 阻断（ICB）治疗显示了这种模式的巨大前景，但仍然只有少数人， 患者对这种治疗方式具有持久的反应。我认为，改变代谢程序， 肿瘤微环境（TME）可能与功能失调的抗肿瘤免疫应答有关。通过揭示这些 因此，通过相互作用，可能会有新的机会来提高免疫治疗的疗效。我创造了一部小说 数据表明，肿瘤模型中的骨髓细胞在TME中摄取显著更多的葡萄糖， 转化的细胞似乎是谷氨酰胺消耗的。肾细胞癌（RCC）的代谢改变 肿瘤的特征是复杂和丰富的免疫细胞浸润。这是由我们的 这些肿瘤浸润性T细胞是代谢受损的，并且具有有限的抗肿瘤活性。 容量尽管ICB提高了RCC患者的生存率，但只有少数患者完全存活。 这些T细胞刺激剂的反应。RCC的独特遗传学可能有助于这一点 上述抑制性TME。在透明细胞RCC中，肿瘤抑制因子von Hippel Lindau（VHL）的缺失 是肿瘤发生的必要事件。此外，在侵袭性II型乳头状RCC的亚组中， 富马酸水合酶（FH）的缺陷或三羧酸循环中的其他缺陷是肿瘤形成所必需的。这些 我的导师WK拉斯梅尔和其他人定义了遗传事件。这些遗传事件在RCC结果中 在致癌转录因子（TF）缺氧诱导因子1 β和2 β的积累中。与 随着这些TF的积累，RCC肿瘤细胞通过减少它们对TF的依赖来改变它们的能量需求。 三羧酸循环和线粒体呼吸，同时增加细胞糖酵解。因此，RCC是 独特地提出进一步研究肿瘤细胞代谢对淋巴和骨髓细胞命运的影响， 功能该项目将应用新型免疫活性、非免疫原性的CRISPR/Cas9模型来研究CRISPR/Cas9基因的表达。 RCC遗传事件（VHL和FH缺失）对免疫浸润和激活的影响。在这些模型中，我 还将研究抑制免疫细胞摄取葡萄糖和谷氨酰胺的不同结果， 在TME中的健身和功能。这项工作将得到补充的研究，采用体外初级 人类RCC类器官模型，以检查遗传和化学扰动对人类的影响， 肿瘤驻留免疫细胞代谢。这项研究将最终阐明肿瘤的异型性 新陈代谢.通过了解异源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抗肿瘤能力的能力。这些 数据将有助于未来的药理学策略，可以提高我们诱导临床显著的 抗肿瘤免疫应答在更大的患者群体中。

项目成果

Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge" (December 4th-5th, 2019, Naples, Italy).

• DOI: 10.1186/s12967-020-02627-y
• 发表时间: 2021-01-06
• 期刊: Journal of translational medicine
• 影响因子: 7.4
• 作者: Ascierto PA;Butterfield LH;Campbell K;Daniele B;Dougan M;Emens LA;Formenti S;Janku F;Khleif SN;Kirchhoff T;Morabito A;Najjar Y;Nathan P;Odunsi K;Patnaik A;Paulos CM;Reinfeld BI;Skinner HD;Timmerman J;Puzanov I
• 通讯作者: Puzanov I

The therapeutic implications of immunosuppressive tumor aerobic glycolysis.

• DOI: 10.1038/s41423-021-00727-3
• 发表时间: 2022-01
• 期刊: Cellular & molecular immunology
• 影响因子: 24.1
• 作者: Reinfeld BI;Rathmell WK;Kim TK;Rathmell JC
• 通讯作者: Rathmell JC