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.

项目摘要/摘要 这是乔纳森·特鲁希略博士的K08职业发展奖申请表，他是一名临床医生 芝加哥大学血液学/肿瘤科讲师。他正在打造自己的职业生涯 内科医生-科学家专注于确定免疫治疗耐药机制以改善患者的预后 癌症患者。他提出的项目将确定肿瘤细胞内在低氧诱导因子的作用 低氧诱导因子-1α和低氧诱导因子-2α活化在肿瘤免疫逃逸和免疫治疗抵抗中的作用癌 尽管进行了密集的治疗，但仍是美国第二大死亡原因。免疫 检查点抑制剂在一些患者中显示出令人印象深刻和持久的临床反应，但大多数 患者对这些免疫疗法没有反应。新出现的数据表明，低氧导致的增加 肿瘤内由缺氧诱导因子-1α和缺氧诱导因子-2α通路介导的信号转导 微环境与T细胞炎症减少和对抗PD-1阻断的抵抗力有关。 肿瘤细胞固有的低氧诱导因子-1α和低氧诱导因子-2α激活对抗肿瘤T细胞应答的影响尚未得到证实 下定决心。这一提议的主要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逸和 免疫治疗耐药。新的黑色素瘤基因工程小鼠模型 已经产生了HIF-1α或HIF-2α的稳定变体的表达，以确定癌细胞是否- 固有的低氧诱导因子-1α或低氧诱导因子-2α激活限制了T细胞在肿瘤组织内的聚集程度，并降低了 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是- 2α通过损害T细胞启动和/或限制效应T细胞在肿瘤中的渗透和功能而发挥作用 微环境。将进行机制研究以确定HIF-1α或HIF-2α途径 激活导致不能积累和激活产生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，肿瘤血管异常可限制 T细胞渗透，或诱导免疫抑制因子，可削弱T细胞反应。这些数据可能 为新型HIF抑制剂和免疫检查点阻断疗法的结合提供理论基础。特鲁希略医生 制定了职业发展计划，以在该奖项期间实现以下目标：1)发展专业知识 在免疫学和基因组学技术和小鼠抗肿瘤免疫模型方面；2)熟练掌握 生物信息学；3)扩大对肾癌的认识，重点是免疫疗法和新技术 低氧诱导因子抑制剂。他建立了一个由他的主要导师托马斯·加杰斯基博士领导的强大的指导委员会， 一位国际知名的癌症免疫学专家。因此，在完成这项提议后，特鲁希略博士 将成为一名专注于癌症免疫学和临床免疫疗法的独立内科科学家。