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Regulated Expression of a Tumor-Associated Antigen Reveals Multiple Levels of T-Cell Tolerance in a Mouse Model of Lung Cancer

¹ Koch Institute and Department of Biology and ² Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts

Requests for reprints: Tyler Jacks, 77 Massachusetts Avenue, E17-517, Cambridge, MA 02139. Phone: 617-253-0262; Fax: 617-253-9863; E-mail: tjacks{at}mit.edu.

Key Words: tumor antigen • T cells • mouse model • lung cancer • immune tolerance

Maximizing the potential of cancer immunotherapy requires model systems that closely recapitulate human disease to study T-cell responses to tumor antigens and to test immunotherapeutic strategies. We have created a new system that is compatible with Cre-LoxP–regulatable mouse cancer models in which the SIY antigen is specifically overexpressed in tumors, mimicking clinically relevant TAAs. To show the utility of this system, we have characterized SIY-reactive T cells in the context of lung adenocarcinoma, revealing multiple levels of antigen-specific T-cell tolerance that serve to limit an effective antitumor response. Thymic deletion reduced the number of SIY-reactive T cells present in the animals. When potentially self-reactive T cells in the periphery were activated, they were efficiently eliminated. Inhibition of apoptosis resulted in more persistent self-reactive T cells, but these cells became anergic to antigen stimulation. Finally, in the presence of tumors overexpressing SIY, SIY-specific T cells required a higher level of costimulation to achieve functional activation. This system represents a valuable tool in which to explore sources contributing to T-cell tolerance of cancer and to test therapies aimed at overcoming this tolerance. [Cancer Res 2008;68(22):9459–68]