Basic Aspects of Tumor Immunology
Many approaches are being explored to determine how to activate T cells specific for tumors. We are interested in how vaccination using tumor antigens with amino acid substitutions leads to increased antitumor responses. We are defining the binding parameters within the MHC-peptide-TCR complex that are necessary to activate tumor-specific T cells. Using mouse models, we showed that amino acid substitutions in a tumor antigen that increase the stability of the MHC-peptide-TCR complex are significantly more potent as tumor vaccines. The improved immunity results from enhanced expansion of T cells specific for the natural tumor antigen. Using cutting-edge technologies, we are extending these studies to determine the limits of the correlation between the stability of the TCR complex and the increased response to tumors. In addition, we are testing which peptide interactions, those with the MHC or those with the TCR, can be altered to elicit the most effective antitumor response. Finally, we have begun new experiments to determine the effects of the microenvironment of the tumor on the T cells elicited by these vaccines. In particular, do low oxygen levels within the tumor impede the cytolytic functions of the T cells.
Jordan, KR, F Crawford, JW Kappler, and JE Slansky. Vaccination of mice with baculovirus-infected insect cells expressing antigenic proteins. In Current Protocols in Immunology, J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach and W. Strober, eds. (United States: John Wiley & Sons), Unit 2.15 (2009).
McWilliams*, JA, RT Sullivan*, KR Jordan*, RH McMahan*, CB Kemmler*, M McDuffie, JE Slansky. T cell tolerance to an endogenous retrovirus-encoded tumor-associated antigen increases with age. Vaccine 26:1863-1873 (2008) [*equal contributors].
Jordan KR, RH McMahan, JZ Oh, MR Pipeling, DM Pardoll, RM Kedl, JW Kappler, JE Slansky. Baculovirus-infected insect cells expressing peptide-MHC complexes elicit protective antitumor immunity. J Immunol 180:188-197 (2008).
McMahan RH and JE Slansky. Mobilizing the low-avidity T cell repertoire to kill tumors. Sem Cancer Biol 17:317-329 (2007).
McMahan RH, JA McWilliams, KR Jordan, SW Dow, DB Wilson, JE Slansky. Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines. J Clin Invest 116:2543-2551 (2006).