A dual role for IFN-gamma in resolving the balance between tumor progression and regression.

Format:

Book

Thesis/Dissertation

Author/Creator:

Beatty, Gregory Lawrence.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Immunology.

0982.

Local Subjects:

0982.

Physical Description:

208 pages

Contained In:

Dissertation Abstracts International 61-10B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Tumor-reactive T lymphocytes can direct the progression of tumor immunity through the secretion of cytokines such as IFN-gamma. IFN-gamma often displays a decisive function in tilting the balance between tumor progression and immune attack in the favor of the immune system. However, several human tumors display a resistance to IFN-gamma suggesting that this may serve as a mechanism to circumvent recognition and elimination by the immune system. In this work, we investigate the function of tumor responsiveness to IFN-gamma in resolving the balance between tumor progression and regression.

Although IFN-gamma has generally been thought to be an essential component of effective tumor immunity, we have found that IFN-gamma has the potential to both discourage tumor outgrowth by inhibiting tumor angiogenesis and promote tumor escape through a reduction in tumor immunogenicity due to the downregulation of an endogenous tumor antigen. The clinical outcome of tumor challenge in the animal models described here is, therefore, dependent on a delicate balance of anti- and pro-tumor activities that is defined by IFN-gamma secreted by tumor-infiltrating T cells. Using the CT26 murine colon carcinoma model, we demonstrate a critical role for IFN-gamma secreted by CD4+ T cells in restraining initial tumor development through the inhibition of tumor angiogenesis. However, despite an initial slowing of tumor growth, the inevitable downregulation of the immunodominant tumor antigen by IFN-gamma promotes a decrease in tumor immunogenicity that is correlated with tumor growth. We compare the findings obtained in the CT26 model to the human papilloma virus (HPV) E6/E7 expressing TC1 tumor model. In this system, we demonstrate a requirement for tumor sensitivity to IFN-gamma for the efficacy of antigen-based immunotherapy. We find that tumor sensitivity to IFN-gamma is not required for inhibition of tumor angiogenesis, but is required for facilitating T cell infiltration into the tumor mass. These results identify a novel role for tumor sensitivity to IFN-gamma and suggest that loss of tumor responsiveness to IFN-gamma may pose an impediment to antigen-based immunotherapy. Nonetheless, these results underscore the importance of communication between T cells and tumor cells in defining the effectiveness of tumor immunity.

Notes:

Source: Dissertation Abstracts International, Volume: 61-10, Section: B, page: 5224.

Supervisor: Yvonne Paterson.

Thesis (Ph.D.)--University of Pennsylvania, 2000.

Local Notes:

School code: 0175.

ISBN:

9780599966178

Access Restriction:

Restricted for use by site license.