Elucidating the role of tumor cell-intrinsic hypoxia inducible factor (HIF)-1α and HIF-2α pathway activation in tumor immune evasion

阐明肿瘤细胞内在缺氧诱导因子（HIF）-1α和HIF-2α途径激活在肿瘤免疫逃避中的作用

• 批准号: 10664693
• 负责人: Jonathan A Trujillo
• 金额: $ 18.84万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-12 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664693
• 关键词: Ablation; Adoptive Transfer; Antibody Therapy; Antigen Presentation; Apoptosis; Award; Bioinformatics; CTLA4 blockade; Cell Survival; Cell physiology; Chicago; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Data; Defect; Dendritic Cells; Development Plans; Doctor of Philosophy; Exclusion; Failure; Flow Cytometry; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genomics; Goals; Hematology; Human; Hypoxia; Hypoxia Inducible Factor; Immune Evasion; Immune checkpoint inhibitor; Immunofluorescence Immunologic; Immunologics; Immunotherapeutic agent; Immunotherapy; Impairment; Infiltration; Inflammation; International; Invaded; K-Series Research Career Programs; Knowledge; Link; Malignant Neoplasms; Mediating; Melanoma Cell; Mentors; Metabolic; Modeling; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Oncology; PD-1 blockade; PTEN gene; Pathway interactions; Patient-Focused Outcomes; Patients; Physicians; Play; Proliferating; Renal Cell Carcinoma; Research; Resistance; Role; Scientist; Series; Signal Induction; System; T cell infiltration; T cell response; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Training; Transgenic Organisms; Transplantation; Tumor Escape; Tumor Expansion; Tumor Immunity; Tumor Promotion; Tumor Tissue; United States; Universities; Variant; anti-CTLA-4 therapy; anti-CTLA4 antibodies; anti-PD-L1; anti-tumor immune response; antigen-specific T cells; cancer cell; cancer genomics; cancer infiltrating T cells; cancer type; career; career development; chemokine; draining lymph node; effector T cell; experimental study; immune activation; immune cell infiltrate; immune checkpoint blockade; improved outcome; in vivo; inhibitor; instructor; loss of function; melanoma; migration; mortality; mouse model; neoplastic cell; novel; programmed cell death protein 1; programs; recruit; resistance mechanism; response; restraint; single-cell RNA sequencing; success; trafficking; transcription factor; transcriptome sequencing; transcriptomics; tumor; tumor immunology; tumor microenvironment

Project Summary/Abstract This is an application for a K08 Career Development Award for Jonathan Trujillo, MD PhD, who is a clinical instructor in the Section of Hematology/Oncology at the University of Chicago. He is building a career as a physician-scientist focused on identifying immunotherapy resistance mechanisms to improve outcomes for patients with cancer. His proposed project will determine the role of tumor cell-intrinsic hypoxia-inducible factor (HIF)-1α and HIF-2α activation in mediating tumor immune evasion and immunotherapy resistance. Cancer remains the second leading cause of mortality in the United States in spite of intensive treatments. Immune checkpoint inhibitors have shown impressive and durable clinical responses in some patients, yet the majority of patients fail to respond to these immunotherapies. Emerging data indicate that increased hypoxia-induced signaling, which is mediated by the hypoxia inducible factor (HIF)-1α and HIF-2α pathways, within the tumor microenvironment is associated with reduced T cell-based inflammation and resistance to anti-PD-1 blockade. The impact of tumor cell-intrinsic HIF-1α and HIF-2α activation on the anti-tumor T cell response has yet to be determined. The overarching hypothesis of this proposal is that cancer cell-intrinsic HIF-1α or HIF-2α activation leads to defective T cell priming and ineffective T cell infiltration, thereby promoting tumor immune evasion and immunotherapy resistance. Novel genetically engineered mouse models of melanoma with conditional expression of a stabilized variant of HIF-1α or HIF-2α have been generated to determine whether cancer cell- intrinsic HIF-1α or HIF-2α activation limits the degree of T cell accumulation within tumor tissue and reduces tumor sensitivity to immune checkpoint inhibitors. The proposed studies will determine whether HIF-1α or HIF- 2α functions by impairing T cell priming and/or by limiting effector T cell infiltration and function in the tumor microenvironment. Mechanistic studies will be performed to determine whether HIF-1α or HIF-2α pathway activation results in failure to accumulate and activate dendritic cells required to generate T cell responses, failure to upregulate chemokines needed for DC or T cell recruitment, aberrant tumor vasculature which can limit T cell infiltration, or induction of immunosuppressive factors that can impair T cell responses. These data may provide rationale for the combination of novel HIF inhibitors and immune checkpoint blockade therapy. Dr. Trujillo has devised a career development plan to accomplish the following goals during this award: 1) develop expertise in immunologic and genomics techniques and mouse models of anti-tumor immunity; 2) become proficient in bioinformatics; 3) to expand knowledge in renal cell carcinoma with a focus on immunotherapeutics and novel HIF inhibitors. He has developed a strong mentoring committee led by his primary mentor Dr. Thomas Gajewski, an internationally renowned expert in cancer immunology. Thus, upon completion of this proposal, Dr. Trujillo will emerge as an independent physician-scientist focused on cancer immunology and clinical immunotherapy.

项目概要/摘要 这是 Jonathan Trujillo 博士的 K08 职业发展奖申请，他是一名临床医生 芝加哥大学血液学/肿瘤学系讲师，他正在建立自己的职业生涯。 医生科学家专注于确定免疫治疗耐药机制以改善结果 他提出的项目将确定肿瘤细胞内在缺氧诱导因子的作用。 (HIF)-1α 和 HIF-2α 激活介导肿瘤免疫逃避和癌症免疫治疗抵抗。 尽管进行了强化治疗，但它仍然是美国第二大死亡原因。 检查点抑制剂在一些患者中显示出令人印象深刻且持久的临床反应，但大多数患者 新出现的数据表明，患者对这些免疫疗法没有反应。 肿瘤内的缺氧诱导因子 (HIF)-1α 和 HIF-2α 通路介导的信号传导 微环境与减少 T 细胞炎症和抗 PD-1 阻断相关。 肿瘤细胞固有的 HIF-1α 和 HIF-2α 激活对抗肿瘤 T 细胞反应的影响尚未确定 该提案的总体假设是癌细胞固有的 HIF-1α 或 HIF-2α 激活。 导致T细胞启动缺陷和T细胞浸润无效，从而促进肿瘤免疫逃避和 具有条件的黑色素瘤的新型基因工程小鼠模型。 HIF-1α 或 HIF-2α 的稳定变体的表达已产生，以确定癌细胞是否 内在的 HIF-1α 或 HIF-2α 激活限制了肿瘤组织内 T 细胞积累的程度，并减少了 肿瘤对免疫检查点抑制剂的敏感性 拟议的研究将确定 HIF-1α 或 HIF-1。 2α 通过损害 T 细胞启动和/或限制效应 T 细胞在肿瘤中的浸润和功能来发挥作用 将进行微环境研究以确定 HIF-1α 或 HIF-2α 途径。 激活导致无法积累和激活产生 T 细胞反应所需的树突状细胞， 未能上调 DC 或 T 细胞募集所需的趋化因子，异常的肿瘤血管系统可能会限制 T 细胞浸润或诱导免疫抑制因子可能会损害 T 细胞反应。 Trujillo 博士为新型 HIF 抑制剂和免疫检查点阻断疗法的结合提供了理论依据。 制定了职业发展计划，以在获奖期间实现以下目标：1）发展专业知识 2）精通免疫学和基因组学技术以及抗肿瘤免疫小鼠模型； 3）扩大肾细胞癌的知识，重点是免疫治疗和新药 他建立了一个由他的主要导师 Thomas Gajewski 博士领导的强大指导委员会， Trujillo 博士是一位国际知名的癌症免疫学专家。 将成为一名专注于癌症免疫学和临床免疫治疗的独立医师科学家。