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

基本信息

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
项目类别：
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

项目摘要

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 此外，我还被列为多项研究的共同发明人。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，重点关注多年来，我的研究在免疫治疗领域变得独一无二。这种独特的技能需要深入的免疫学知识和知识。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 K99/R00 奖项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。在卢雄斌博士（癌症生物学）等知名科学家的指导下进行研究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) 患者患有高微卫星不稳定性 (MSI-H) 肿瘤，其中很大一部分因此，新途径中额外的检查点抑制剂（CPI）效果不佳。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这一点在本提案中，我将确定此类免疫疗法的可能目标以及潜在陷阱。在我的 JCI 见解中，白细胞介素 33 (IL-33) 及其受体 STimulation 2 (ST2) 在 CRC 免疫治疗中的应用。发表了初步数据，我确定表达 ST2 的肿瘤相关巨噬细胞 (TAM) 会阻碍因此，我认为表达 ST2 的 TAM 在抑制中发挥着重要作用。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。