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，他在肿瘤免疫学方面发展了独特的技能和癌症免疫疗法。通过我的研究生和博士后研究，我建立了一个富有成效的轨道 - 记录七个第一/联合首选的作者手稿，共有18个顶级同行评审研究和评论的记录论文，包括：自然纳米技术，ACS Nano，自然通讯，临床杂志研究，癌症免疫学研究和JCI Insight。此外，我被列为几个专利申请。发展/培训：我的长期目标是确立自己是一名独立研究人员关于癌症免疫疗法。多年来，我的研究在免疫疗法领域变得独一无二正在桥接多个学科。这种独特的技能需要在免疫学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，因为我将被指导成为独立在诸如Xiongbin Lu博士（癌症生物学）之类的非常成熟的科学家的指导下，研究人员的研究人员和Sophie Paczesny博士（免疫学和免疫疗法）。我还将与Chi Zhang博士密切合作（生物信息学解卷）和肯尼斯·邓恩（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了前所未有的临床肿瘤回归结直肠癌（CRC）患者具有微卫星不稳定性高（MSI-H）肿瘤，很大一部分患者几乎没有改善。那是新途径中的其他检查点抑制剂（CPI）需要；肿瘤微环境（TME）细胞浸润和固体因素的投资将揭示可能的靶标以及这种免疫疗法的潜在陷阱。在此提案中，我将确定角色 CRC免疫疗法中的白介素-33（IL-33）及其接收器刺激2（ST2）。在我的JCI洞察力中发表的初步数据，我确定表达肿瘤相关巨噬细胞（TAM）障碍的ST2 CD8+ T细胞响应。因此，我假设表达TAMS的ST2在抑制中起着至关重要的作用抗原特异性的T细胞介导的免疫回报，靶向这些TAM可以作为潜力新颖的免疫检查点途径。此外，我还将研究ST2在CRC肿瘤细胞和激活IL-33/ST2途径导致癌症免疫疗法抗性的贡献。最后，我会的使用IL-33陷阱融合蛋白来评估IL-33/ST2热阻断的翻译电位免费局部和全身IL-33或作为替代方法ST2小分子抑制剂，该抑制剂将阻止 IL-33与其ST2受体复合物的功能结合，这些药物与其他检查点结合免疫疗法。通过该奖项的支持将大大增加我在早期获得R01的可能性职业阶段。