Peter A. Savage, Ph.D.

Tumor-associated T cell responses in mouse models of spontaneous cancer
Research Summary

Our laboratory studies the immunological forces that modulate the development and progression of cancer.  How does the immune system influence the development of neoplasia arising from different cell types, in different organs?  How can the immune system be harnessed to induce cancer regression?  To study these and other questions, we utilize mouse models of spontaneous cancer for the study of basic immunological processes, and as pre-clinical models for the study of cancer immunotherapy.  Current major projects include:

1.  Development and function of tumor-associated regulatory T cells

CD4+ Foxp3+ regulatory T cells (Treg) are important modulators of immune homeostasis and organ-specific immune tolerance.  Despite major advances in our understanding of Treg biology in recent years, many fundamental aspects of Treg function remain poorly understood. In particular, what are the antigens driving Treg development in the thymus and activation in the periphery, what is the cellular context in which Tregs exert their activity, and what are the effector mechanisms by which Treg mediate their function?  In addition, much of what is known about Treg function has come from the study of immune homeostasis at steady state, in healthy animals.  In contrast, our studies focus on the role of Tregs in the modulation of cancer initiation and progression.  Do Tregs promote tumor development by suppressing ongoing anti-tumor T cell responses, or do they modulate cancer progression, invasion, and metastasis by regulating the inflammatory milieu and stromal composition within the tumor environment?

In order to address these and other important questions regarding Treg function in the tumor environment, we have identified a population of Tregs expressing highly conserved T cell receptors (TCRs) found recurrently in the tumor infiltrate of mice with prostate cancer.  We have generated transgenic mice expressing this Treg TCR, and are using T cells from these mice to study Treg development and homeostasis, antigen specificity, function in the tumor microenvironment, and response to immunotherapy.

2.  Evolution and function of CD8+ histone H4-reactive tumor-associated T cell responses

For most types of cancer, very little is known about the antigens that elicit CD4+ and CD8+ tumor-associated T cell responses, and the functional role of tumor-infiltrating T cells in shaping cancer development and progression.  For example, are tumor-infiltrating T cells reactive to antigens expressed by tumor cells, or are they reactive to antigens expressed by stromal cells such as fibroblasts, endothelial cells, and macrophages?  Is the intent of these T cells to eliminate neoplastic cells, or do they participate in the modulation of the tumor microenvironment in a way that we do not yet fully appreciate? 

Previously, in our studies of prostate cancer in TRAMP mice (Savage et al., Science 319:215, 2008), we have identified an endogenous CD8+ T cell response reactive to a peptide from histone H4.  The spontaneous T cell response to histone H4 is surprising, in that histone H4 does not fit into the major classes of tumor antigens.  Since histone H4 is abundantly and ubiquitously expressed in every nucleated cell, why is the immune system not tolerant to histone H4, and why does the development of prostate cancer in these mice trigger a histone H4-reactive T cell response?  Furthermore, although histone H4-reactive T cells are MHC class I-restricted CD8+ T cells, the cells do not develop classical CD8+ “killer” cell effector functions, suggesting that they may have other unique functions that are not yet understood.  To address these and other questions, we are studying the affinity selection, response kinetics, gene expression program, and function of tumor-infiltrating histone H4-reactive T cells in TRAMP mice, and are dissecting the cellular and molecular mechanisms that modulate the response.

In addition to studies in mouse models, we are developing a parallel research program in which insights gained from mouse models are used to guide studies and therapeutic intervention in human cancer patients, and hypotheses developed from observations in patients can be investigated systematically and prospectively in mouse models.

Selected Papers

Yee, C.,  Savage, P.A., Lee, P.P., Davis, M.M., and Greenberg, P.D. (1999).  Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers.  Journal of Immunology 162, 2227-2234.

Savage, P.A., Boniface, J.J., and Davis, M.M. (1999).  A kinetic basis for T cell receptor repertoire selection during an immune response.  Immunity 10, 485-492.

Lee, P.P., Yee, C., Savage, P.A., Fong, L., Brockstedt, D., Weber, J.S., Johnson, D., Swetter, S., Thompson, J., Greenberg, P.D., Roederer, M., and Davis, M.M. (1999).  Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients.  Nature Medicine 5, 677-685.

Savage, P.A. and Davis, M.M. (2001).  A kinetic window constricts the T cell receptor repertoire in the thymus.  Immunity 14, 243-252.

Savage, P.A., Vosseller, K., Kang, C., Larimore, K., Riedel, E., Wojnoonski, K., Jungbluth, A.A., and Allison, J.P. (2008).  Recognition of a ubiquitous self antigen by prostate cancer-infiltrating CD8+ T lymphocytes.  Science 319, 215-220.