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.

项目总结/摘要 这是Jonathan特鲁希略（医学博士）的K 08职业发展奖申请，他是一名临床医学博士。 芝加哥大学血液学/肿瘤学系讲师。他正在建立一个职业生涯， 医生科学家专注于确定免疫疗法抗性机制，以改善 癌症患者。他提出的项目将确定肿瘤细胞内源性缺氧诱导因子的作用 （HIF）-1α和HIF-2α活化介导肿瘤免疫逃避和免疫治疗抗性。癌 在美国，尽管进行了强化治疗，但它仍然是第二大死亡原因。免疫 检查点抑制剂在一些患者中显示出令人印象深刻的和持久的临床反应，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，增加缺氧诱导 肿瘤内由缺氧诱导因子（HIF）-1α和HIF-2α通路介导的信号传导 微环境与减少的基于T细胞的炎症和对抗PD-1阻断的抗性相关。 肿瘤细胞内源性HIF-1α和HIF-2α激活对抗肿瘤T细胞应答的影响还有待进一步研究。 测定这一提议的首要假设是癌细胞内源性HIF-1α或HIF-2α激活 导致有缺陷的T细胞引发和无效的T细胞浸润，从而促进肿瘤免疫逃避， 免疫治疗抵抗。条件性黑色素瘤的新型基因工程小鼠模型 已经产生了HIF-1α或HIF-2α的稳定变体的表达，以确定癌细胞- 内源性HIF-1α或HIF-2α激活限制了肿瘤组织内T细胞积聚的程度， 肿瘤对免疫检查点抑制剂的敏感性。拟议的研究将确定是否HIF-1α或HIF-1 α， 2α通过损害T细胞引发和/或限制效应T细胞浸润和肿瘤中的功能发挥作用 微环境将进行机制研究以确定HIF-1α或HIF-2α通路是否 活化导致不能积累和活化产生T细胞应答所需的树突细胞， 不能上调DC或T细胞募集所需的趋化因子，异常的肿瘤血管系统， T细胞浸润，或诱导免疫抑制因子，可损害T细胞反应。这些数据可以 为新型HIF抑制剂和免疫检查点阻断疗法的组合提供了理论基础。特鲁希略医生 我制定了一个职业发展计划，在此期间实现以下目标：1）发展专业知识 免疫学和基因组学技术以及抗肿瘤免疫的小鼠模型; 2）精通 生物信息学; 3）扩大肾细胞癌的知识，重点是免疫治疗和新的 HIF抑制剂。他已经建立了一个强大的指导委员会，由他的主要导师托马斯加博斯基博士领导， 国际知名的癌症免疫学专家。因此，在完成本提案后，特鲁希略博士 将成为一名独立的医生，科学家，专注于癌症免疫学和临床免疫治疗。