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

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 和癌症免疫疗法。在我的研究生和博士后研究期间，我建立了一条富有成效的道路- 记录有7篇第一/联合第一作者手稿和总共18篇顶级同行评议的研究和评论 论文包括：自然纳米技术，美国计算机学会纳米，自然通讯，临床杂志 调查、癌症免疫学研究和JCI洞察。此外，我还被列为几个项目的共同发明人 专利申请。 发展/培训：我的长期目标是让自己成为一名独立的研究员，专注于 关于癌症免疫疗法。多年来，我的研究在免疫治疗领域变得独一无二，因为我 我在多个学科之间架起桥梁。这一独特的技能组合需要深入了解免疫学和 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 菲尔德。K99/R00奖将帮助我实现目标，因为我将被引导成为一名独立的人 研究人员在著名科学家的指导下，如卢雄斌博士(癌症生物学) 和苏菲·帕切斯尼博士(免疫学和免疫疗法)。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：尽管检查点免疫疗法观察到前所未有的临床肿瘤消退 存在微卫星不稳定性高(MSI-H)肿瘤的结直肠癌(CRC)患者，很大比例 患者得到的改善很少，甚至没有改善。因此，新途径中的其他检查点抑制物(CPI)是 需要；肿瘤微环境(TME)细胞浸润物和可溶性因子的研究将有助于阐明 这种免疫疗法的可能靶点以及潜在的陷阱。在这项提案中，我将确定 IL-33及其受体刺激因子2(ST2)在结直肠癌免疫治疗中的应用在我的JCI洞察中 发表的初步数据表明，ST2表达肿瘤相关巨噬细胞(TAMs)阻碍了 CD8+T细胞反应。因此，我推测ST2在抑制TAMs的表达中起着重要作用 抗原特异性T细胞介导的免疫反应和靶向这些TAM可能是一种潜在的 新的免疫检查点途径。此外，我还将研究ST2在结直肠癌细胞中的作用以及 激活IL-33/ST2通路在肿瘤免疫治疗抵抗中的作用最后，我会 用IL-33-TRAP融合蛋白检测IL-33/ST2治疗阻滞剂的翻译潜能 游离的局部和全身IL-33，或者作为替代方法，使用ST2小分子抑制剂来阻断 IL-33与其ST2受体复合体的功能性结合以及这些药物与其他检查点的结合 免疫疗法。通过这个奖项的支持将极大地增加我早日获得R01的可能性 职业生涯阶段。

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.