Peter A. Savage, Ph.D.

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

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

Research Interests

The goal of our research program is to understand how the immune system modulates the development, progression, and metastasis of cancer.  In particular, our research focuses on the study of cancer-associated T lymphocyte populations.  Specifically, what are the antigens recognized by T cells infiltrating primary tumors in vivo, what are the functions of these T cell populations, how do these cells shape tumor development, and how can the immune system be harnessed to induce cancer regression?  Current major projects include:

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

Foxp3+ regulatory T cells (“Tregs”) are critical for the suppression of autoimmunity and the regulation of immune homeostasis, and are often prevalent in human cancers. Many emerging therapeutic strategies for the treatment of cancer have focused on the modulation or depletion of Tregs concomitant with vaccination or cell transfer, in order to stimulate effective anti-tumor immune responses. Yet despite this intense interest in modulating Tregs in the context of cancer, major fundamental questions regarding the biology of Tregs remain unanswered. Specifically, the developmental origins, antigen specificity, and in situ function of tumor-infiltrating Tregs are not well understood.  Using model systems that we have developed, our goal is to elucidate the fundamental rules by which Tregs function in the context of cancer.  In essence, we aim to understand the “life cycle” of a tumor-infiltrating Treg, starting from its development in the thymus or periphery, its circulation throughout the body, its activation and recruitment into a developing neoplasm, and the functional role that the cell plays in shaping tumor development and metastasis.

2.  Function of Aire-dependent Tregs in immune tolerance

The transcriptional regulator Aire (Autoimmune Regulator) drives the ectopic expression of peripheral tissue antigens by thymic epithelial cells, and is critical for the maintenance of immune tolerance.  Recently, we have demonstrated that the thymic development of some naturally occurring Treg specificities is critically dependent on Aire (Malchow et al. 2013).  These findings suggest that Aire plays a dual role in immune tolerance, by driving the deletion of autoreactive cells specific for peripheral antigens, and by facilitating the thymic development of Tregs.  Our lab is currently investigating the molecular and cellular mechanisms by which Aire-dependent processes impact negative selection and Treg development. 

Lab Members:

Julian Berger, Undergraduate
Daniel Leventhal, Graduate Student
Sven Malchow, Postdoctoral Fellow
Saki Nishi, Research Technologist
Peter Savage, Principal Investigator
Lynn Shen, Graduate Student

Selected Papers

Malchow, S., Leventhal, D.S., Nishi, S., Fischer, B.I., Shen, L., Paner, G.P., Amit, A.S., Kang, C., Geddes, J.E., Allison, J.P., Socci, N.D., and Savage, P.A. (2013).  Aire-dependent thymic development of tumor-associated regulatory T cells.  Science, In Press.

Savage, P.A., Malchow, S., Leventhal, D.S. (2013).  Basic principles of tumor-associated regulatory T cells. Trends In Immunology, 34. 33-40.

Donkor, M.K., Sarkar, A., Savage, P.A., Franklin, R.A., Johnson, L.K., Jungbluth, A.A., Allison, J.P., and Li, M.O. (2011).  Cell-autonomous TGF-b signaling suppresses T cell surveillance of tumor development.  Immunity 35, 123-134.

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.

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

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., 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.

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.