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-?- 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.

Public Health Relevance

The goal of this project is to examine the roles of IL-9-secreting Th9 cells in antitumor response in vivo in mice bearing large, established tumors. We hypothesize that the tumor-specific Th9 subset may be a superior effector T-cell subset than the Th1 subset for cancer immunotherapy, due to their capacity to persist longer, home effectively to tumors, covert to IFN-?- and granzyme B-secreting effector T cells, and kill bystander antigen-loss-variant tumors after adoptive transfer in vivo. In this application we propose a series of in vitro and in vivo studies to examine the potential and mechanism of Th9-indced antitumor responses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K99)
Project #
1K99CA190910-01
Application #
8804489
Study Section
Subcommittee G - Education (NCI)
Program Officer
Schmidt, Michael K
Project Start
2015-02-10
Project End
2017-01-31
Budget Start
2015-02-10
Budget End
2016-01-31
Support Year
1
Fiscal Year
2015
Total Cost
$92,275
Indirect Cost
$6,835
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Zhao, Yinghua; Chu, Xiao; Chen, Jintong et al. (2016) Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat Commun 7:12368