Pseudo-hypoxic contributions to the tumor microenvironment in kidney cancer

假性缺氧对肾癌肿瘤微环境的贡献

基本信息

批准号：
10546439
负责人：
Melissa M Wolf
金额：
$ 3.29万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546439
关键词：
3-Dimensional Address Affect Antigen-Antibody Complex Antitumor Response Area CD8B1 gene Cancer Biology Cell Communication Cell Energetics Cell Hypoxia Cell Line Cell physiology Cells Cellular Metabolic Process Characteristics Clear cell renal cell carcinoma Complement Complex Consumption Data Defect Dependence Development Disease Management Environment Event Fine needle aspiration biopsy Genetic Genetic Transcription Glucose Growth Homeostasis Human Hypoxia Hypoxia Inducible Factor Immune Immune Evasion Immunologic Surveillance Immunooncology Immunotherapy Impairment Infiltration Inflammatory Investigation Knock-out Learning Link Lymphocyte Suppression Malignant Neoplasms Mediating Metabolic Metabolism Modality Modeling Mus Mutation Myelogenous Myeloid-derived suppressor cells Nutrient availability Organoids Oxygen Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Phenotype Population Population Heterogeneity Renal carcinoma Resistance Role Shapes Signal Pathway Signal Transduction T-Lymphocyte Testing Time Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-associated macrophages Tumor-infiltrating immune cells Ubiquitination VHL gene VHL protein Work aerobic glycolysis anti-tumor immune response cancer cell functional disability immune cell infiltrate immune checkpoint blockade immune function improved in vivo in vivo Model mitochondrial metabolism normoxia novel recruit response single cell analysis single nucleus RNA-sequencing therapy resistant tool transcription factor transcriptome translational study tumor tumor metabolism tumor microenvironment tumor progression

项目摘要

ABSTRACT Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is characterized by deregulated hypoxic signaling, metabolic defects, and complex immune cell infiltrate in the tumor microenvironment (TME). Loss of the oxygen sensing gene, von Hippel Lindau (VHL), is a critical early event in ccRCC pathogenesis and promotes stabilization of hypoxia inducible (transcription) factors (HIF) that upregulate pro-growth signaling pathways, including aerobic glycolysis, regardless of oxygen availability. This phenomenon is termed “pseudo- hypoxia.” The most frequent immune types affecting ccRCC are functionally impaired CD8 tumor infiltrating lymphocytes (CD8 TIL) and metabolically enhanced tumor associated macrophages (TAM). Advancements in immune oncology have led to improved overall patient outcomes with immune checkpoint blockade (ICB) therapy; however, current modalities do not result in durable responses for the majority of ccRCC patients. I propose that features linked to pseudo-hypoxic signaling promote alterations in cancer cell energetic requirements that impact immune cell function in the TME and revealing these aspects may provide new opportunities for therapy. My preliminary data indicate that Vhl loss favors a mature TAM myeloid phenotype with enhanced mitochondrial metabolism in murine RCC, and this result is consistent with enhanced metabolism observed in the myeloid compartment of human ccRCC. Additionally, TAM suppression of CD8 TIL may be enhanced by specific interactions with cancer cells, though exact TAM functions are not understood. In this proposal, I will test the hypothesis that pseudo-hypoxic signals from cancer cells in the TME preferentially support a metabolically active TAM subset that promotes CD8 TIL suppression and that inhibiting TAM activity will enhance the CD8 TIL response to ICB therapy. To test the cancer cell pseudo- hypoxic effect on TAM function I have developed a fine needle aspiration-based patient-derived organoid (FNA- PDO) model that recapitulates key factors of the TME in human tumors. I will also employ a pair of murine syngeneic Renca cell line models (Vhl WT and Vhl KO) to address the impact of pseudo-hypoxia on the TME in vivo. I will: (1) Test if pseudo-hypoxia supports a unique TAM phenotype with distinct metabolism; and (2), Test the role of TAM in T cell suppression and ICB response. Ultimately, these studies will advance our current understanding of kidney cancer biology by demonstrating mechanisms that shape the TME and highlighting new strategies to improve immunotherapy.

抽象的透明细胞肾细胞癌 (ccRCC) 是最常见的肾癌类型，其特点是失调肿瘤微环境（TME）中缺氧信号、代谢缺陷和复杂的免疫细胞浸润。氧传感基因 von Hippel Lindau (VHL) 的缺失是 ccRCC 发病机制中的一个关键早期事件，促进缺氧诱导（转录）因子 (HIF) 的稳定，从而上调促生长信号途径，包括有氧糖酵解，无论氧气供应情况如何，这种现象被称为“伪-糖酵解”。缺氧。影响 ccRCC 的最常见的免疫类型是功能受损的 CD8 肿瘤浸润。淋巴细胞（CD8 TIL）和代谢增强的肿瘤相关巨噬细胞（TAM）的进展。免疫肿瘤学通过免疫检查点阻断 (ICB) 改善了患者的总体预后治疗；然而，目前的治疗方法并未对大多数 ccRCC 患者产生持久的缓解。提出与假性缺氧信号相关的特征促进癌细胞能量的改变影响 TME 中免疫细胞功能的要求并揭示这些方面可能会提供新的我的初步数据表明，Vhl 缺失有利于成熟的 TAM 骨髓表型。小鼠肾细胞癌中线粒体代谢增强，这一结果与代谢增强一致另外，在人 ccRCC 的骨髓室中观察到，TAM 对 CD8 TIL 的抑制可能是这样的。通过与癌细胞的特定相互作用而增强，尽管具体的 TAM 功能尚不清楚。提议，我将检验以下假设：TME 中癌细胞发出假性缺氧信号优先支持代谢活跃的 TAM 子集，促进 CD8 TIL 抑制，并且抑制TAM活性将增强CD8 TIL对ICB治疗的反应以测试癌细胞伪-。缺氧对 TAM 功能的影响我开发了一种基于细针抽吸的患者来源的类器官 (FNA- PDO）模型概括了人类肿瘤中 TME 的关键因素，我还将使用一对小鼠。同基因 Renca 细胞系模型（Vhl WT 和 Vhl KO），用于解决假性缺氧对 TME 的影响我将：（1）测试假性缺氧是否支持具有不同代谢的独特 TAM 表型；以及（2）测试 TAM 在 T 细胞抑制和 ICB 反应中的作用最终，这些研究将推进我们目前的研究。通过展示塑造 TME 的机制并强调新的机制来了解肾癌生物学改善免疫治疗的策略。