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

• 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
• 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

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 缺氧。”影响 ccRCC 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）。进步 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。我 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 治疗的机会。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 在人 ccRCC 的骨髓室中观察到。此外，TAM 对 CD8 TIL 的抑制可能是 尽管 TAM 的确切功能尚不清楚，但它通过与癌细胞的特定相互作用而增强。在这个 提议，我将测试 TME 中癌细胞发出的假缺氧信号的假设 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。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。我还将雇用一对小鼠 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 体内。我将：（1）测试假性缺氧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，这些研究将推进我们目前的 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。