Development of a T cell based cancer immunotherapy by using the induced pluripotent stem cell
Open Access
- Author:
- Lei, Fengyang
- Graduate Program:
- Microbiology and Immunology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- April 23, 2013
- Committee Members:
- Jianxun Song, Dissertation Advisor/Co-Advisor
Jianxun Song, Committee Chair/Co-Chair
Neil David Christensen, Committee Member
Todd Schell, Committee Member
John Warren Wills, Committee Member
Jiyue Zhu, Special Member - Keywords:
- stem cell
T cell
differentiation
immunotherapy - Abstract:
- Cancer is one of the leading health issues that has caused tremendous impacts. Conquering cancer is imminent and finding more potent treatments to cancer is also urgent. In searching for novel anti-cancer regimens, recently, a new concept of cancer immunotherapy has been proposed. It is found that by using adoptive T cell transfer (ACT)-based immunotherapy, tumor regression can be achieved. However, a major problem of this strategy is the shortage of T cells for transfer. Previous work has shown that stem cells are good candidates for generating T cell for therapeutic purposes; however, there are many hurdles existed. The recent discovery of the induced pluripotent stem (iPS) cell technology hints that iPS cells are potential substitutes of natural stem cells for generating T cells being used in cancer immunotherapy. The hypothesis of my research is iPS cell is identical to other stem cells in the context of T lineage differentiation, and furthermore, iPS cell can be engineered and induced into antigen specific T cell to bolster the tumor immune surveillance. In the first study, it is observed iPS cells are able to differentiate into conventional T cells after in vitro Notch signaling pathway ligand stimulation. In vitro developed iPS cells express general T cell markers, respond to costimulatory signal activation and reconstitute the T cell pools of the recipient lymphopenic mice. Following this, a second work showed antigen-specific T cells are induced from iPS cells through the T cell receptor (TCR) signal stimulation. In short, genetically modifying iPS cells with antigen-specific TCR can promote the development of corresponding T cells in vivo and developed T cells are functional in terms of responding to antigen stimulation and managing tumor growth. Further analyses suggested that both Notch and TCR signals may be involved, in a synergistic manner, in inducing iPS cells to develop into T cells; and probably, this process is mediated by the transforming growth factor (TGF)-β signaling pathway. These studies have initially supported our hypothesis however both extensive and intensive studies are still needed to further test our central hypothesis. In conclusion, my dissertation study served as the first series of proof-of-concept work to investigate the feasibility of an iPS cell-based, personalized cancer immunotherapy.