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

总结/摘要： 我是印第安纳州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 和癌症免疫疗法。在我的研究生和博士后研究中，我建立了一个富有成效的轨道- 7篇第一/共同第一作者手稿和18篇顶级同行评审研究和评论 论文，包括：自然纳米技术，ACS纳米，自然通讯，临床杂志 调查，癌症免疫学研究和JCI Insight。此外，我还被列为几项发明的共同发明人。 专利申请。 发展/培训：我的长期目标是成为一名独立的研究人员， 癌症免疫疗法这些年来，我的研究在免疫治疗领域变得独一无二， 我在多学科之间架起桥梁。这种独特的技能需要深入的免疫学知识， 免疫治疗以及对生物信息学，纳米技术和生物医学工程的扎实理解 领域K99/R 00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 在非常知名的科学家如Xiongbin Lu博士（癌症生物学）的指导下， Sophie Paczesny博士（免疫学和免疫疗法）。我还将与张驰博士密切合作， （生物信息学解卷积）和Kenneth Dunn博士（CODEX®技术和显微镜）。 研究：尽管检查点免疫疗法观察到前所未有的临床肿瘤消退， 结直肠癌（CRC）患者中，有很大比例的微卫星不稳定性高（MSI-H）肿瘤， 患者几乎没有改善。因此，新途径中的其他检查点抑制剂（CPI）是 需要;肿瘤微环境（TME）细胞浸润和可溶性因子的研究将揭示 可能的目标以及这种免疫疗法的潜在陷阱。在这份提案中，我将确定 白细胞介素-33（IL-33）及其受体STimulation 2（ST 2）在CRC免疫治疗中的作用。在我的JCI Insight中 发表的初步数据，我建立了表达ST 2的肿瘤相关巨噬细胞（TAMs）阻碍 CD 8 + T细胞应答。因此，我假设表达TAM的ST 2在抑制TCAM的表达中起重要作用。 抗原特异性T细胞介导的免疫应答，靶向这些TAM可以作为一种潜在的 新的免疫检查点途径。此外，我还将研究ST 2对CRC肿瘤细胞的作用， 这可能是激活IL-33/ST 2通路导致癌症免疫疗法抗性的贡献。最后要 使用IL-33-trap融合蛋白评估IL-33/ST 2治疗性阻断的翻译潜力， 游离的局部和全身IL-33，或作为替代方法，使用ST 2小分子抑制剂， IL-33与其ST 2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 免疫疗法通过这个奖项的支持将大大增加我获得R 01的可能性， 职业阶段。

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.