Th9 cells as a promising effector T-cell subset for cancer therapy

描述（由申请人提供）：我获得了博士学位。2009年毕业于中国药科大学肿瘤免疫学专业。2010年，我以博士后研究员的身份加入了庆毅博士的实验室，继续我的癌症免疫学研究生涯。在这3.5年的博士后培训期间，我开发了一个创新和重要的领域， 肿瘤免疫学，阐明IL-9在肿瘤免疫中的潜在作用，并探索使用IL-9产生的T细胞过继性癌症免疫治疗。我有一个优秀的出版记录，有12篇第一作者的文章（例如Lu Y et al，PNAS 2014，J Clin Invest 2012，Gene Therapy 2010，Autoimmunity 2010，Endocrine- Related Cancer 2009; Vaccine 2009 and Clincal and Vaccine Immunology 2009）和10篇第二作者和19篇合著的文章在同行评审的高影响力期刊上。到目前为止，我已经接受了强有力的培训，以建立我的肿瘤免疫学，癌症免疫治疗和肿瘤生物学的知识和技术。 目前，我是克利夫兰诊所Lerner研究所癌症生物学系的博士后研究员，如果获奖，该研究所将致力于支持我的K99/R 00提案。我的近期职业目标是在癌症研究中获得翻译免疫治疗的独立终身职位。我的长期目标是在实验室中开发新的治疗药物和策略，并将其转化为临床。在目前的建议中，我假设与Th 1细胞相比，肿瘤特异性Th 9亚群可能是癌症免疫治疗的上级效应T细胞亚群，因为其能够持续更长时间，有效地归巢肿瘤，并在体内过继转移后转化为分泌IFN-γ和GrzB的效应T细胞。我相信，在我经验丰富的导师易博士的全力投入和支持拟议项目的理想机构环境下，我有必要的研究资源来促进这个杰出项目的成功。我打算利用这个K99/R 00奖项专注于以下具体的职业发展目标： 在为期2年的K99指导阶段，我计划进一步获得研究计划设计的新策略，当前进展的知识，以及来自我的导师，初级教师教育计划和国家/国际会议的癌症免疫治疗领域的基本技术。我将集中我的研究工作在K99指导期间专注于特定目标1，以研究为什么转移的Th 9细胞持续时间更长，以及Th 9细胞是否显示出具有体内自我更新能力的分化程度较低的T细胞亚群的核心分子特征。我的导师易博士，贝琪B。de Windt是癌症生物学系的主席，是多发性骨髓瘤肿瘤免疫学和免疫治疗领域的主要研究者之一。2008年，易博士指导下的博士后研究员获得了K99/R 00资助，并在两年后成功获得了独立的终身职位。此外，易博士在肿瘤生物学、分子生物学和信号转导方面也有所需的专业知识，他将进一步在分子生物学和信号转导方面对我进行培训。这种额外的培训对我来说是必要的， 目的1d，特别是，研究肿瘤特异性Th 9细胞是否由于自分泌IL-9达特激活细胞中的STAT（1，3和5），PI 3 K/AKT和ERK信号通路而成为具有体内自我更新能力的分化程度较低的长寿细胞。K99指导阶段的培训将支持我成为一名成功的独立研究者，从事基于Th 9细胞的翻译型癌症免疫治疗研究，并从科学上将易博士的研究领域--以独特型蛋白和DKK 1为靶点的骨髓瘤免疫治疗分开。 在接下来的R 00奖阶段，我计划在著名的免疫学或癌症免疫治疗部门获得癌症研究中转化免疫治疗的独立终身职位。我计划在翻译研究方面获得高级技能/知识/经验。我的研究计划建立在我以前的IL-9/肿瘤免疫学工作的逻辑上，专注于特定目标2，以检查IL-9如何有助于Th 9细胞转化为细胞毒性效应细胞和Th 9细胞介导的体内肿瘤破坏，以及特定目标3，以检查为什么转移肿瘤特异性Th 9细胞可以杀死旁观者抗原丢失变体肿瘤细胞的机制。K99指导阶段的分子生物学额外培训将使我能够独立研究IL-9在转移后体内Th 9转化为完全效应细胞中的分子机制，如Specific Aim 2d所述。这些创新和机制研究将揭示Th 9细胞介导的抗肿瘤免疫的机制，因此对于在人类癌症中使用肿瘤特异性T细胞亚群开发更有效的免疫疗法非常重要。通过实现目标2和3，我将成为利用肿瘤特异性Th 9细胞治疗致命癌症的癌症免疫疗法领域的独立新研究者。在这个R 00独立阶段，我将为癌症免疫疗法转化研究项目准备R 01或R21或类似资金的额外申请。

DESCRIPTION (provided by applicant): I obtained a Ph.D. in 2009 from China Pharmaceutical University, training in tumor immunology. In 2010, I joined Dr. Qing Yi's laboratory as a postdoctoral research fellow to continue my cancer immunology research career. During this 3.5 year postdoctoral training period, I developed an innovative and significant area in tumor immunology, elucidating the potential role of IL-9 in tumor immunity and exploring the use IL-9-producing T cells for adoptive cancer immunotherapy. I have an excellent publication record, with 12 first-authored articles (e.g. Lu Y et al, PNAS 2014, J Clin Invest 2012, Gene Therapy 2010, Autoimmunity 2010, Endocrine- Related Cancer 2009; Vaccine 2009 and Clincal and Vaccine Immunology 2009) and with 10 second-authored and 19 co-authored articles in peer-reviewed, high-impact journals. Up to date, I have received strong training to build my knowledge and techniques of tumor immunology, cancer immunotherapy and tumor biology. Currently, I am a postdoctoral fellow in the Department of Cancer Biology of Lerner Research Institute of Cleveland Clinic, and the institute is committed to supporting my K99/R00 proposal, if awarded. My immediate career objective is to attain an independent tenure-track position in translational immunotherapy in cancer research. My long-term goal is to develop novel therapeutic agents and strategies in the laboratory and translate them into the clinic. In current proposal, I hypothesize that compared with Th1 cells, the tumor- specific Th9 subset may be a superior effector T-cell subset for cancer immunotherapy, due to its capacity to persist longer, home effectively to tumors, and convert to IFN-γ- and GrzB-secreting effector T cells after adoptive transfer in vivo. I believe that with the full commitment of my experienced successful mentor Dr. Yi and the ideal institutional environment to support the proposed project, I have the necessary research resources to facilitate the success of this outstanding project. I intend to use this K99/R00 award to concentrate on the following specific career development objectives: During the 2-year K99 mentored phase, I plan to further acquire new strategies for research program design, knowledge of current advances, and fundamental techniques in the field of cancer immunotherapy from my mentor, junior faculty education programs, and national/international meetings. I will concentrate my research work in the K99 mentored period focusing on Specific Aim 1 to examine why transferred Th9 cells persist longer and whether Th9 cells display a core molecular signature of a less differentiated T cell subset with the capacity for self-renewal in vivo. My mentor Dr. Yi, the Betsy B. de Windt Endowed Chair of the Department of Cancer Biology, is one of the leading investigators in the fields of tumor immunology and immunotherapy in multiple myeloma. In 2008, a postdoctoral fellow under Dr. Yi's mentorship was awarded a K99/R00 grant and successfully attained an independent tenure-track position 2 years later. In addition, Dr. Yi also has the needed expertise in tumor biology, molecular biology and signal transduction, and he will further train me in molecular biology and signal transduction. This additional training is necessary for me to carry out Specific Aim 1d, and in particular, to investigate whether tumor-specific Th9 cells become less differentiated, long-lived cells with the capacity for self-renewal in vivo due to autocrine IL-9 tat activates the STAT(1, 3 and 5), PI3K/AKT, and ERK signaling pathways in the cells. The K99 mentored phase training will support me to become a successfully independent investigator in Th9 cell-based translational cancer immunotherapy research and scientifically separate from Dr. Yi's research field of myeloma immunotherapy targeting idiotype protein and DKK1. During the following R00 award phase, I plan to attain an independent tenure-track position in translational immunotherapy in cancer research in a renowned immunology or cancer immunotherapy department. I plan to obtain advanced skills/knowledge/experience in translational research. My research plan builds logically on my prior IL-9/tumor immunology work, focusing on Specific Aim 2 to examine how IL-9 contributes to the conversion of Th9 cells to cytotoxic effector cells and to Th9 cell-mediated tumor destruction in vivo, and Specific Aim 3 to examine the mechanisms underlying why transfer of tumor-specific Th9 cells can kill bystander antigen-loss-variant tumor cells. The additional training in molecular biology in K99 mentored phase will allow me to independently investigate molecular mechanisms of IL-9 in Th9 conversion to full effector cells in vivo after transfer, as proposed in Specific Aim 2d. These innovative and mechanistic studies will shed light on the mechanisms underlying Th9 cell-mediated antitumor immunity, and are therefore highly significant and important for the development of more effective immunotherapies using tumor-specific T-cell subsets in human cancers. By accomplishing Aims 2 and 3, I will become established as an independent new investigator in the field of cancer immunotherapy utilizing tumor-specific Th9 cells to treat the deadly cancer. In this R00 independent phase, I will prepare an additional application for R01 or R21 or comparable funding for a cancer immunotherapy translational research project.