T lymphocyte mediated control of cancer, vaccine strategies, T lymphocyte tolerance

My research interests focus on the role of the cellular immune response in the control of cancer. CD8+, or cytotoxic, T lymphocytes (CTL) have been implicated as critical components of the immune response to tumors with the ability to directly lyse tumor cells as well as secrete cytokines which suppress tumor growth. Approaches that lead to successful T cell-mediated control of tumor progression, however, are inhibited by the development of T lymphocyte tolerance toward potential tumor antigens that also represent "self" antigens. Thus, my interests are in developing strategies to recruit tumor-specific CD8+ T cells under conditions of self tolerance for the immunotherapy of cancer.

The model system we use to study the CD8+ T cell response to cancer is the Simian virus 40 oncoprotein large T antigen. T antigen serves as both a transforming protein, inducing tumor progression when expressed as a transgene in mice, and contains multiple CD8+ T cell-recognized epitopes designated epitopes I, II/III, IV and V. This model provides a platform to assess approaches that target immunity against a well characterized "self" antigen in the context of progressing cancer. We are interested in defining which epitopes are important for control of tumors that arise in T antigen transgenic mice. Our recent studies have revealed that: 1) targeting the H2-Kb-restricted epitope IV of T antigen is associated with the control of tumor progression in T antigen transgenic mice, 2) Epitope IV-specific CD8+ T cells can be detected at the tumor site using a fluorescently-labeled tetrameric Kb/epitope IV reagent, 3) These cells have both lytic function and secrete interferon-gamma in response to antigen, and 4) T antigen expression in the peripheral tissues limits the responsiveness of CD8+ T cells specific for each of the T antigen epitopes I, II/III, IV and V, but the timing of tolerance onset varies for each epitope. In particular, the onset of tolerance to epitope IV correlated directly with the appearance of tumors. This suggests that a window of opportunity exists for immunization against tumors and that epitope selection is critical for the immunotherapy of cancer. We are interested, therefore, in determining if CD8+ T cells can be recruited from within this limited T cell repertoire that can effectively mediate control of tumor progression. This research involves a number of approaches aimed at enhancing the surviving CD8+ T cell response to the subdominant epitope V in T antigen transgenic mice for the control of progressing tumors.