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.

抽象的清除细胞肾细胞癌（CCRCC）是最常见的肾癌类型，其特征是失调肿瘤微环境（TME）中的低氧信号传导，代谢缺陷和复杂的免疫细胞浸润。氧气传感基因的丧失，von Hippel Lindau（VHL）是CCRCC发病机理和促进缺氧诱导（转录）因子（HIF）的稳定，该因子上调了促增长信号传导途径，包括有氧糖酵解，无论氧气供应如何。这种现象被称为“伪缺氧。“影响CCRCC的最常见的免疫类型在功能上受损的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）。进步免疫肿瘤学导致免疫检查点封锁（ICB）改善了总体患者预后治疗;但是，当前的方式不会导致大多数CCRCC患者的持久反应。我与伪催化信号相关的特征的提案促进癌细胞能量的改变影响TME中免疫细胞功能并揭示这些方面的要求可能会提供新的治疗机会。我的初步数据表明VHL损失有利于成熟的TAM髓样表型随着鼠RCC中的线粒体代谢增强，该结果与增强的新陈代谢一致在人CCRCC的髓样室中观察到。另外，TAM抑制CD8可能是尽管尚不清楚确切的TAM功能，但通过特定的与癌细胞相互作用增强。在这个提案，我将检验以下假设：TME中的癌细胞中的催化信号优先支持代谢活性的TAM子集，该子集促进CD8 TIL抑制，并抑制TAM活性将增强CD8对ICB治疗的反应。测试癌细胞伪对TAM功能的缺氧作用I已经形成了基于精细的针刺的患者衍生的类器官（FNA- PDO）模型，该模型概括了人类肿瘤中TME的关键因素。我还将雇用一对鼠 Syngeneic Renca细胞系模型（VHL WT和VHL KO），以解决伪避风氧对TME在TME中的影响体内。我将：（1）测试假催眠症是否支持具有独特代谢的独特TAM表型；（2），测试 TAM在T细胞抑制和ICB反应中的作用。最终，这些研究将推动我们的当前通过演示塑造TME并突出新的机制来了解肾癌生物学改善免疫疗法的策略。