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: 10366086
• 负责人: KEVIN VAN DER JEUGHT
• 金额: $ 11.87万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366086
• 关键词: Affect; Antibodies; Antigen Presentation; Antigens; Award; Binding; Bioinformatics; Biological Assay; Biomedical Engineering; CD47 gene; CD8-Positive T-Lymphocytes; Cancer Biology; Cell Line; Cells; Chimeric Proteins; Clinical; Colon; Colorectal Cancer; Communication; Complex; Data; Development; Discipline; Disease; Environment; Goals; Human; Immune checkpoint inhibitor; Immune response; Immune system; Immunology; Immunosuppression; Immunotherapy; Indiana; Infiltration; Interleukin Activation; Interleukins; Investigation; Journals; Knockout Mice; Knowledge; Lead; Legal patent; Light; Literature; Lymphoblastic Leukemia; Malignant Neoplasms; Manuscripts; Mediating; Memory; Microsatellite Instability; Microscopy; Modeling; Molecular; Molecular Profiling; Mus; Nanotechnology; Nature; Outcome; PTPNS1 gene; Paper; Pathway interactions; Patients; Phagocytosis; Phenotype; Play; Postdoctoral Fellow; Publishing; Rectal Cancer; 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; base; 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; macrophage; men; nano; neoplastic cell; novel; 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.

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