Investigating immune surveillance, tolerance, and therapy in cancer

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 immune therapeutic strategies. Current model systems largely relied on chemically-induced and spontaneous tumors in immunodeficient mice or on transplanted tumors. Such systems are limited because they fail to reproduce the complex interactions that exist among an emerging tumor, its microenvironment and the multiple elements of an intact immune system. We created a new system that is compatible with Cre-loxP-regulatable mouse cancer models in which the defined antigen SIY is specifically over-expressed in tumors, mimicking clinically-relevant tumor-associated antigens. To demonstrate the utility of this system, we characterized SIYreactive T cells in the context of lung adenocarcinoma, revealing multiple levels of antigenspecific T cell tolerance that serve to limit an effective anti-tumor 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 over- expressing SIY, SIY-specific T cells required a higher level of costimulation to achieve functional activation.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2009

Author dc:creator

• Cheung, Ann F

Advisor dc:contributor.advisor

• Tyler Jacks.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/46809

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/46809