The recently identified cytokine IL-21 augments anti-CD3 mediated CD8+ T cell activation. However, the effect of IL-21 on tumor-antigen induced CD8+ T cell responses remains unknown. The goals of this proposal are to understand the molecular and cellular mechanisms underlying the effects of IL-21 on tumor antigen-specific CD8+ T cell responses and utilize this information to generate effective T cells for adoptive cellular therapy of cancer. The preliminary characterizations suggest that IL-21 enhances activation, proliferation, differentiation and sustenance of tumor antigen specific CD8+ T cell responses in vivo. The ability of IL-21 to regulate naive CD8+ T cell responses was confirmed using an in vitro system in which TCR transgenic CD8+ T cells (OT-I) are evaluated for their molecular and cellular response to IL-21 treatment. By extending these investigations we will test the hypothesis that IL-21 treatment will generate large numbers of long-lived effector CD8+ T cells and promote adoptive immunity against cancer.
Four specific aims are proposed.
In aim1, we will test how IL-21 augments naive and anergized OT-I T cell activation and proliferation upon antigen stimulation, the role for STAT1, STAT3 and STAT5 in the IL-21 effect will be determined. The generation of effector functions such as type 1 cytokine expression and cytotoxicity are critical for immunological control of tumor cells.
In aim 2, we will determine how IL-21 promotes differentiation in na?ve and anergized OT-I T cells, by addressing the specific role of STAT1, STAT3 and STAT5 in OT-I effector development. Immunological memory is a desirable objective for most cancer immunotherapies.
In aim 3, we will test the ability of IL-21 to generate memory in OT-I T cells and establish a role for STAT1, STAT3 and/or STAT5 in the memory formation. Finally, in aim 4, we will utilize this information to test the effectiveness of IL-21 alone or in combination with cytokines such as IL-15 and/or IL-12 in producing OT-I T cells that result inefficacy against established cancer by adoptive therapy. The insights provided by these investigations are likely to develop rational use of IL-21 alone or in combination with other cytokines for the therapy of cancer, infectious diseases, autoimmunity and transplantation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104645-03
Application #
7011154
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Muszynski, Karen
Project Start
2004-02-13
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$285,439
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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