Type 17 CD8 T Cell (Tc17): Studies on Its Functional Plasticity and Application in Immunotherapy

  • Yen, Hung-Rong (PI)
  • Huang, Ching Tai (CoPI)
  • Lin, Chun-Yen (CoPI)
  • Lin, Yung-Chang (CoPI)

Project: National Health Research InstitutesNational Health Research Institutes Grants Research

Project Details

Abstract

The primary goal of this research project is to understand the anti-tumor immunity and mechanism of adoptively transferred IL-17 secreting CD8 cells (Tc17) cells to tumors. Cancer has ranked as the top cause of death in Taiwan since 1982, and more than 300,000 people are living with cancers in Taiwan or even much more worldwide. Adoptive T cell transfer immunotherapy is a promising approach for cancer immunotherapy by selective stimulating, activating and expanding tumor-reactive T cells ex vivo that are then transferred back to the patients. Early attempts of adoptive immunotherapy met with some success; however, harnessing the exquisite potency and persistence of T cells to treat human malignancy has proven challenging. Two fundamental principles for the deployment of adoptive immunotherapy are the requirements to isolate and expand T cells specific for tumor antigens and the persistence of transferred tumor-reactive T cells in vivo after adoptive transfer. In our published and preliminary data, we found that antigen-specific IL-17 producing Tc17 can functionally convert to IFN-g producing cells, robustly expand, and then mediate autoimmunity or antitumor immunity after adoptively transferred in to mice that express cognate antigen in autoimmune model or tumor model, respectively. The current proposal, through a series of in vitro experiments mirroring invivo environment as well as adoptive transfers in antigen-specific tumor-bearing models, will study the cellular and molecular mechanisms of CD8 Tc17 cells response to tumors and of the process through which cells alter their cytokine-producing potential, which may allow the development of a better strategy for adoptive immunotherapy for cancer patients. This proposal is designed to test the hypothesis that adoptive transfer of Tc17 leads to tumor inhibition through functional plasticity as well as anti-apoptotic property. To reach the goal, three SPECIFIC AIMS are proposed: SPECIFIC AIM 1. To determine the anti-tumor immune response of antigen-specific Tc17 CD8 T cells in tumor-bearing mice and the cytokine requirements for this effect. SPECIFIC AIM 2. To understand cellular and molecular mechanism regulating subset plasticity in Tc17 cells. SPECIFIC AIM 3. To investigate the mechanism involved in an increased Tc17 persistence in vitro and in vivo. Successful completion of this work could transform adoptive T cell transfer for the effective treatment of cancer patients, and shed novel insight into fundamental aspects of CD8 function and differentiation. THE LONG-TERM OBJECTIVE is to integrate multi-disciplines including but not limited to cellular, biochemical and molecular knowledge of T cell immunity as a basis for ultimately translational and clinical research to make cancer preventable, curable, or chronically manageable. This will be achieved by: 1. Establishment of a research platform and strategies for adoptive transfer T cell immunotherapy by which specific immune response could be turn on or off through engineering T cells. 2. Fundamental knowledge about the potency and persistence of CD8 T cell immunity in tumor microenvironment and the application of that knowledge to enhance anti-tumor immunity 3. Comprehensive mechanistic dissection of T cell plasticity which could lead to interventions in which endogenous CD8 could be reprogrammed to a desired phenotype, without the need for adoptive T cell transfer to tackle tumor evasion or escape.

Project IDs

Project ID:PG10012-0224
External Project ID:NHRI-EX101-10124SC
StatusFinished
Effective start/end date01/01/1231/12/12

Keywords

  • Immunotherapy
  • Tumor Immunology
  • Cancer
  • Adoptive T Cell Transfer Immunotherapy

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