Targeting the IL-33/ST2 Pathway in Colorectal Cancer Immunotherapy

结直肠癌免疫治疗中靶向 IL-33/ST2 通路

• 批准号: 10732792
• 负责人: KEVIN VAN DER JEUGHT
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732792
• 关键词: Affect; Antibodies; Antigen Presentation; Antigens; Award; Binding; Bioinformatics; Biological Assay; Biomedical Engineering; CD47-SIRPα; CD8-Positive T-Lymphocytes; Cancer Biology; Cell Line; Cells; Chimeric Proteins; Clinical; Collaborations; Colon; Colorectal Cancer; Communication; Complex; Data; Development; Discipline; Environment; Goals; Human; Immune checkpoint inhibitor; Immune response; Immune system; Immunology; Immunosuppression; Immunotherapy; Indiana; Infiltration; Interleukin Activation; Interleukins; Investigation; Journals; Knockout Mice; Knowledge; Legal patent; Literature; Lymphoblastic Leukemia; Macrophage; Malignant Neoplasms; Manuscripts; Mediating; Memory; Microsatellite Instability; Microscopy; Modeling; Molecular; Molecular Profiling; Mus; Nanotechnology; Nature; Outcome; Paper; Pathway interactions; Patients; Phagocytosis; Phenotype; Play; Postdoctoral Fellow; Productivity; Publishing; Rectal Cancer; Recurrent disease; Reporting; Research; Research Peer Review; Research Personnel; Resistance; Role; SHPS-1 protein; Sampling; Scientist; Signal Transduction; Solid; T cell response; T-Lymphocyte; Technology; Therapeutic; Therapeutic Uses; Training; Treatment Protocols; Tumor Antigens; Tumor-associated macrophages; Universities; Woman; anti-PD-1; anti-PD1 therapy; antigen-specific T cells; cancer cell; cancer immunotherapy; cancer stem cell; cancer vaccination; career; cell mediated immune response; checkpoint therapy; clinical investigation; colon cancer patients; cytokine; cytotoxic CD8 T cells; cytotoxicity; deprivation; design; experimental study; immune checkpoint; improved; insight; interest; leukemia/lymphoma; men; nano; neoplastic cell; novel; programs; receptor; response; skills; small molecule inhibitor; stem cells; tissue stress; transcriptome sequencing; translational potential; tumor; tumor growth; tumor immunology; tumor microenvironment; vaccination strategy

Summary/Abstract: I am a postdoctoral fellow at Indiana University who has developed a unique set of skills in tumor immunology and cancer immunotherapy. Throughout my graduate and postdoctoral studies, I established a productive track- record with seven first/co-first author manuscripts and a total of 18 top-tier peer-reviewed research and review papers, including: Nature Nanotechnology, ACS Nano, Nature Communications, The Journal of Clinical Investigation, Cancer Immunology Research and JCI Insight. Furthermore, I am listed as co-inventor on several patent applications. Development/Training: My long-term goal is to establish myself as an independent researcher with the focus on cancer immunotherapy. Throughout the years, my research became unique in the immunotherapy field as I am bridging multiple disciplines. This unique skill set requires in-depth knowledge in immunology and immunotherapy as well as solid understanding in bioinformatics, nanotechnology and the biomedical engineering field. The K99/R00 award will help in achieving my goal, as I will be guided towards becoming an independent investigator under the guidance of extremely well-established scientists such as Dr. Xiongbin Lu (cancer biology) and Dr. Sophie Paczesny (immunology and immunotherapy). I will also closely collaborate with Dr. Chi Zhang (bioinformatics deconvolution) and Dr. Kenneth Dunn (CODEX® Technology and microscopy). Research: Despite unprecedented clinical tumor regression observed with checkpoint immunotherapy in colorectal cancer (CRC) patients harboring microsatellite instability high (MSI-H) tumors, a large proportion of patients receive little to no improvement. Thus, additional checkpoint inhibitors (CPI) in new pathways are needed; investigation of tumor microenvironment (TME) cell infiltrates and soluble factors will shed light on possible targets as well as potential pitfalls to such immunotherapies. In this proposal, I will determine the role of the interleukin-33 (IL-33) and its receptor STimulation 2 (ST2) in CRC immunotherapy. In my JCI Insight published preliminary data, I established that ST2 expressing tumor associated macrophages (TAMs) hamper CD8+ T-cell responses. I therefore hypothesize that ST2 expressing TAMs play an essential role in suppressing antigen-specific T-cell mediated immune responses and that targeting these TAMs could serve as a potential novel immune checkpoint pathway. Moreover, I will also investigate the role of ST2 on CRC tumor cells and the contribution of activating the IL-33/ST2 pathway leading to cancer immunotherapy resistance. Finally, I will assess the translational potential of IL-33/ST2 therapeutic blockade using the IL-33-trap fusion protein to trap free local and systemic IL-33 or as an alternative approach a ST2 small molecule inhibitor that will block the functional binding of IL-33 to its ST2 receptor complex, and these agents in combination with other checkpoint immunotherapy. Support through this award will greatly increase my likelihood to obtain an R01 at an early career stage.

摘要/摘要： 我是印第安纳大学的博士后研究员，在肿瘤免疫学方面发展了一套独特的技能 和癌症免疫治疗。在我的研究生和博士后研究中，我建立了一条富有成效的道路—— 创下七篇第一/共同第一作者手稿和总共 18 项顶级同行评审研究和评审的记录 论文，包括：Nature Nanotechnology、ACS Nano、Nature Communications、The Journal of Clinical 调查、癌症免疫学研究和 JCI 洞察。此外，我被列为多个项目的共同发明人 专利申请。 发展/培训：我的长期目标是使自己成为一名独立研究员，重点关注 关于癌症免疫治疗。多年来，我的研究在免疫治疗领域变得独一无二，因为我 正在弥合多个学科。这种独特的技能需要深入的免疫学知识和 免疫疗法以及对生物信息学、纳米技术和生物医学工程的扎实理解 场地。 K99/R00 奖将有助于实现我的目标，因为我将被引导成为一个独立的人 在 Lu Xiongbin Lu 博士（癌症生物学）等知名科学家的指导下进行研究 和 Sophie Paczesny 博士（免疫学和免疫治疗）。我也将与张驰博士密切合作 （生物信息学反卷积）和 Kenneth Dunn 博士（CODEX® 技术和显微镜）。 研究：尽管在检查点免疫疗法中观察到前所未有的临床肿瘤消退 结直肠癌 (CRC) 患者携带微卫星不稳定性高 (MSI-H) 肿瘤，很大一部分 患者几乎没有任何改善。因此，新途径中的额外检查点抑制剂（CPI）是 需要；对肿瘤微环境（TME）细胞浸润和可溶性因子的研究将揭示 此类免疫疗法的可能目标以及潜在陷阱。在这个提案中，我将确定角色 CRC 免疫治疗中白细胞介素 33 (IL-33) 及其受体 STimulation 2 (ST2) 的研究。在我的 JCI 见解中 发表了初步数据，我确定表达 ST2 的肿瘤相关巨噬细胞 (TAM) 会阻碍 CD8+ T 细胞反应。因此，我假设表达 ST2 的 TAM 在抑制 抗原特异性 T 细胞介导的免疫反应，并且针对这些 TAM 可以作为潜在的 新型免疫检查点通路。此外，我还将研究ST2对CRC肿瘤细胞的作用以及 激活 IL-33/ST2 通路导致癌症免疫治疗耐药性的贡献。最后，我会 使用 IL-33-trap 融合蛋白捕获 IL-33/ST2 治疗阻断的转化潜力 游离局部和全身 IL-33 或作为替代方法，使用 ST2 小分子抑制剂来阻断 IL-33 与其 ST2 受体复合物的功能性结合，以及这些药物与其他检查点的组合 免疫疗法。通过该奖项的支持将大大增加我尽早获得 R01 的可能性 职业生涯阶段。