Rewired Metabolism Regulates Vessel Normalization and Immunosuppression

重新连接代谢调节血管正常化和免疫抑制

• 批准号: 9888335
• 负责人: Arun Sreekumar
• 金额: $ 61.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888335
• 关键词: Animals; Area; Biological Response Modifiers; Blood Vessels; Branched-Chain Amino Acids; Breast; Breast Melanoma; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinic; Clinical; Collaborations; Complex; Coupled; Data; Endothelium; Energy Metabolism; Enzymes; Etiology; Follow-Up Studies; Genetic; Genetic Engineering; Glycolysis; Goals; HIF1A gene; Handedness; Heterogeneity; Hypoxia; Immune; Immunization; Immunocompetent; Immunocompromised Host; Immunologic Surveillance; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Interferon Type II; Knockout Mice; Kynurenic Acid; Kynurenine; Light; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Nature; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Pericytes; Permeability; Pharmacology; Phenotype; Process; Proteins; Regulation; Research; Resistance; Resistance development; Signal Transduction; Structure; Succinates; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Transferase; Treatment Protocols; Tryptophan Metabolism Pathway; Tumor Immunity; Tumor-infiltrating immune cells; Warburg Effect; alpha ketoglutarate; base; blood perfusion; cancer cell; cancer type; checkpoint therapy; combinatorial; cytokine; design; enzyme pathway; hypoxia inducible factor 1; immune checkpoint; immune checkpoint blockade; immune function; immunoregulation; improved; in vivo; inhibitor/antagonist; knock-down; malignant breast neoplasm; melanoma; metabolomics; mortality; mouse model; novel; patient response; patient subsets; resistance mechanism; response; standard of care; therapeutic target; therapy resistant; tumor; tumor growth; tumor immunology; tumor metabolism; tumor microenvironment; tumor progression; tumor-immune system interactions

Project Summary Multiple hallmarks distinguish tumors from their normal counterparts. Among these are escape of immune-surveillance and aberrant metabolism (increased glycolysis). Each of these hallmarks has been extensively investigated. Significant progress has been made, especially with the recent emergence of anti- immune checkpoint therapies. However, these therapies still benefit a subset of patients, with efficacy seen only in few cancer types. This reflects the heterogeneity seen between tumors that constantly evolve resistance mechanisms to promote tumor progression. In collaboration with Dr. Sreekumar our long-term goal is to overcome treatment resistance and metastasis in breast and other cancers by integrating our expertise in the areas of tumor immunology and metabolism. In this context, our metabolomics data coupled with follow up studies have highlighted the importance of tryptophan metabolism especially the kynurenine axis in regulating tumor immune interactions. Among the kynureine pathway enzymes, we identified Kynurenine Amino Transferase (AADAT) to be elevated in aggressive basal like tumors and significantly associated with poor clinical outcome in patients and negatively associated with patient’s response to immune therapy in melanoma. AADAT converts KYN to kynurenic acid, in the process using α ketoglutarate, a key component of TCA) as the co-substrate. Our preliminary data demonstrates that AADAT single-handedly regulates energy metabolism in the tumors and immune cell infiltration in the microenvironment potentially mediated via HIF 1α and its consequent effect on vessel normalization (VN), a homeostatic process involving improved pericyte attachment to endothelium, increased blood perfusion, de-creased vessel permeability, and consequently reduced hypoxia. We had earlier demonstrated a novel mutually regulatory loop between VN and immune stimulation in tumor microenvironment that drove the tumor either into a hot” state with self-reinforcing VN and immune cell infiltration or into a “cold” state “stuck” with poorly-developed vessels and minimally infiltrated immune cells and resistant to therapies. Moreover, AADAT depletion also led to activation of IFNγ signaling in cancer cells, further activating anti-tumor immunity. Based on all of the above, we hypothesize that AADAT promotes cancer progression and therapeutic resistance by stimulating immune suppression and energy metabolism by regulating HIF α expression and activity. Our specific aims are: Aim 1: To determine the mechanisms underpinning AADAT’s immunosuppressive functions in various immunocompetent breast cancer and melanoma models. Aim 2: Determine mechanism of action of AADAT by modulating intra-tumoral HIF1α signaling axis. Aim 3 Determine if genetic depletion or pharmacological inhibition of AADAT sensitizes breast cancer and melanoma to immune checkpoint blockade therapies (ICBT). The impact of our study is to mark AADAT as a distinct regulator of immune and metabolism axes, in the tumor and surrounding microenvironment which if proven will reveal a single therapeutically actionable target for aggressive cancers.

项目摘要 多种标志将肿瘤与其正常对应物区分开来。其中， 免疫监视和异常代谢（糖酵解增加）。每一个特征都是 广泛调查。已经取得了重大进展，特别是最近出现了反 免疫检查点疗法。然而，这些疗法仍然使一部分患者受益，并观察到了疗效 仅在少数癌症类型中。这反映了在不断进化的肿瘤之间看到的异质性 耐药机制，以促进肿瘤进展。与Sreekumar博士合作，我们的长期目标是 是通过整合我们的专业知识， 肿瘤免疫学和代谢领域。在这种情况下，我们的代谢组学数据加上随访 研究强调了色氨酸代谢的重要性，特别是犬尿氨酸轴在调节 肿瘤免疫相互作用在犬尿氨酸途径酶中，我们鉴定了犬尿氨酸氨基 转移酶（AADAT）在侵袭性基底样肿瘤中升高，并与不良 患者的临床结局，并与患者对黑色素瘤免疫治疗的反应呈负相关。 AADAT将KYN转化为犬尿烯酸，在此过程中使用α酮戊二酸（TCA的关键组分）作为 共底物。我们的初步数据表明，AADAT单手调节能量代谢， 微环境中的肿瘤和免疫细胞浸润可能通过HIF 1α及其介导 对血管正常化（VN）的后续影响，这是一种涉及改善周细胞附着的稳态过程 增加血液灌注，降低血管通透性，从而减少缺氧。 我们早先已经证明了肿瘤中VN和免疫刺激之间的一种新的相互调节回路 使肿瘤进入“热”状态的微环境，具有自我增强的VN和免疫细胞 浸润或进入“冷”状态，“卡住”发育不良的血管和最低限度浸润的免疫细胞， 对治疗有抵抗力此外，AADAT耗竭还导致癌细胞中IFNγ信号传导的激活， 进一步激活抗肿瘤免疫。基于以上所有，我们假设AADAT促进癌症 通过刺激免疫抑制和能量代谢， 调节HIF α的表达和活性。我们的具体目标是：目标1：确定机制 支持AADAT在各种免疫活性乳腺癌中的免疫抑制功能， 黑素瘤模型。目的2：确定AADAT通过调节肿瘤内HIF 1 α的作用机制 信号轴目的3确定AADAT的遗传缺失或药物抑制是否会使乳腺癌致敏 癌症和黑色素瘤的免疫检查点阻断疗法（ICBT）。我们研究的影响是 AADAT作为免疫和代谢轴的独特调节剂，在肿瘤和周围组织中 如果被证实，它将揭示侵袭性癌症的单一治疗可操作靶点。