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Peter Savage

TitleAssociate Professor
InstitutionUniversity of Chicago
DepartmentPathology
AddressChicago IL 60637
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    Collapse Overview 
    Collapse overview
    Regulation of immune tolerance and anti-tumor immunity

    The goal of our research program is to understand the cellular and molecular mechanisms regulating immune tolerance and the immune response to cancer. Current major projects include:

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

    Foxp3+ regulatory T (Treg) cells 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, fundamental questions regarding the biology of tumor-associated Tregs remain unanswered. Specifically, the developmental origins, antigen specificity, and in situ function of tumor-infiltrating Tregs are not well understood. Using mouse models of prostate cancer (Malchow et al Science 2013) and carcinogen-induced head-and-neck squamous cell carcinoma, 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. Antigen specificity of thymus-derived Treg cells

    A large body of indirect evidence suggests that thymus-derived Treg (tTreg) cells recognize autologus antigens. However, the major self-antigens recognized by Treg cells have remained largely undefined, representing a major barrier to the understanding of immune regulation. Recently, in collaboration with Dr. Erin Adams at the University of Chicago, we identified natural Treg cell ligands in mice (Leonard, Gilmore, et al. Immunity 2017). We found that two recurrent Treg cell clones, one prevalent in prostate tumors and the second associated with prostatic autoimmune lesions, recognized distinct non-overlapping MHC class-II-restricted peptides derived from the same prostate-specific protein. Notably, this protein is frequently targeted by autoantibodies in experimental models of prostatic autoimmunity. Based on these findings, we propose a model in which Treg cell responses at peripheral sites converge on those self proteins that are most susceptible to autoimmune attack, and we suggest that this link may be exploited as a generalizable strategy to identify the Treg cell antigens relevant to human autoimmunity. Moving forward, we are using this model system to define the role of cognate antigen in coordinating Treg development and peripheral homeostasis, to characterize endogenous antigen-specific Treg cell populations at steady state and in disease contexts using pMHC tetramers, and to understand the molecular basis of ligand recognition by tTreg cells.

    3. Aire and the establishment of immune tolerance

    The promiscuous expression of tissue-restricted antigens in the thymus, driven in part by Autoimmune Regulator (Aire), is essential for the protection of peripheral tissues from autoimmune attack. Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3+ Treg cells (Malchow et al. Science 2013), suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms. In recent work (Malchow et al. Immunity 2016), our examination of autoimmune lesions in Aire-/- mice revealed an unexpected third possibility. We found that the predominant conventional T cell clones infiltrating target lesions express antigen receptors that are preferentially expressed by Foxp3+ Treg cells in Aire+/+ mice. Our results reveal that a primary mechanism by which Aire functions is to ensure that distinct autoreactive T cell specificities differentiate into the Treg cell lineage. Dysregulation of this process results in the emergence of "T-rogues" - Treg-biased specificities that are mis-directed into the T conventional subset and "go rogue" in the absence of Aire.

    4. Role of dendritic cells in the development and function of Treg cells

    The recognition of self antigen is critical for many aspects of Treg cell biology, including development, homeostasis, anatomical distribution, and function. However, little is known about the identity of the cell types that present self antigen for recognition by Treg cells. The identity of the "dance partners" that interface with Treg cells at various anatomical sites is likely to reveal new insights into Treg cell biology and immune regulation. In a recent study, we identified a pivotal role for dendritic cells (DCs) in coordinating the development and homeostasis of an archetypal population of Aire-dependent organ-specific Treg cells (Leventhal et al., Immunity 2016). The thymic development of this Treg population required antigen presentation and co-stimulatory signals provided by DCs, implying that Aire-dependent antigen must be transferred from medullary thymic epithelial cells to DCs. In the periphery, the activation and enrichment of organ-specific Treg cells in the organ-draining lymph nodes required CCR7-dependent migratory DCs, implying a unique role for migratory DCs in supporting the peripheral activation of organ-specific Treg cells. Our results demonstrate that the development and peripheral regulation of organ-specific Treg cells are dependent on antigen presentation by DCs, implicating DCs as key mediators of organ-specific immune tolerance.


    Collapse Biography 
    Collapse education and training
    Stanford University School of Medicine, Stanford, CAPhD04/2000Cancer Biology
    University of California Berkeley, Berkeley, CA09/2004Cancer Immunology
    Memorial Sloan-Kettering Cancer Center, New York, NY06/2009Cancer Immunology
    University of VirginiaBA1993Biochemistry
    Collapse awards and honors
    2001 - 2004Postdoctoral Fellow, Damon Runyon Cancer Research Fund
    2010 - 2011Young Investigator Award, Cancer Research Foundation
    2010 - 2012Investigator Award, Cancer Research Institute

    Collapse ORNG Applications 
    Collapse Websites

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. MacNabb BW, Kline DE, Albright AR, Chen X, Leventhal DS, Savage PA, Kline J. Negligible Role for Deletion Mediated by cDC1 in CD8+ T Cell Tolerance. J Immunol. 2019 May 01; 202(9):2628-2635. PMID: 30902900.
      View in: PubMed
    2. Chao JL, Savage PA. Unlocking the Complexities of Tumor-Associated Regulatory T Cells. J Immunol. 2018 01 15; 200(2):415-421. PMID: 29311383.
      View in: PubMed
    3. Leonard JD, Gilmore DC, Dileepan T, Nawrocka WI, Chao JL, Schoenbach MH, Jenkins MK, Adams EJ, Savage PA. Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen. Immunity. 2017 07 18; 47(1):107-117.e8. PMID: 28709804.
      View in: PubMed
    4. Malchow S, Leventhal DS, Lee V, Nishi S, Socci ND, Savage PA. Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage. Immunity. 2016 05 17; 44(5):1102-13. PMID: 27130899.
      View in: PubMed
    5. Leventhal DS, Gilmore DC, Berger JM, Nishi S, Lee V, Malchow S, Kline DE, Kline J, Vander Griend DJ, Huang H, Socci ND, Savage PA. Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells. Immunity. 2016 Apr 19; 44(4):847-59. PMID: 27037189.
      View in: PubMed
    6. Lee V, Savage PA. Close Encounters of the Tertiary Kind. Immunity. 2015 Sep 15; 43(3):418-20. PMID: 26377895.
      View in: PubMed
    7. Kreymborg K, Haak S, Murali R, Wei J, Waitz R, Gasteiger G, Savage PA, van den Brink MR, Allison JP. Ablation of B7-H3 but Not B7-H4 Results in Highly Increased Tumor Burden in a Murine Model of Spontaneous Prostate Cancer. Cancer Immunol Res. 2015 Aug; 3(8):849-54. PMID: 26122284.
      View in: PubMed
    8. Chen X, Fosco D, Kline DE, Meng L, Nishi S, Savage PA, Kline J. PD-1 regulates extrathymic regulatory T-cell differentiation. Eur J Immunol. 2014 Sep; 44(9):2603-16. PMID: 24975127.
      View in: PubMed
    9. Nalle SC, Kwak HA, Edelblum KL, Joseph NE, Singh G, Khramtsova GF, Mortenson ED, Savage PA, Turner JR. Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease. Sci Transl Med. 2014 Jul 02; 6(243):243ra87. PMID: 24990882.
      View in: PubMed
    10. Savage PA, Leventhal DS, Malchow S. Shaping the repertoire of tumor-infiltrating effector and regulatory T cells. Immunol Rev. 2014 May; 259(1):245-58. PMID: 24712470.
      View in: PubMed
    11. Savage PA. Tumor antigenicity revealed. Trends Immunol. 2014 Feb; 35(2):47-8. PMID: 24439426.
      View in: PubMed
    12. Malchow S, Leventhal DS, Savage PA. Organ-specific regulatory T cells of thymic origin are expanded in murine prostate tumors. Oncoimmunology. 2013 Jul 01; 2(7):e24898. PMID: 24073374.
      View in: PubMed
    13. Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, Amit AS, Kang C, Geddes JE, Allison JP, Socci ND, Savage PA. Aire-dependent thymic development of tumor-associated regulatory T cells. Science. 2013 Mar 08; 339(6124):1219-24. PMID: 23471412.
      View in: PubMed
    14. Jain N, Liu H, Artz AS, Anastasi J, Odenike O, Godley LA, Joseph L, Marino S, Kline J, Nguyen V, Schouten V, Kunnavakkam R, Larson RA, Stock W, Ulaszek J, Savage PA, Wickrema A, van Besien K. Immune reconstitution after combined haploidentical and umbilical cord blood transplant. Leuk Lymphoma. 2013 Jun; 54(6):1242-9. PMID: 23088744.
      View in: PubMed
    15. Savage PA, Malchow S, Leventhal DS. Basic principles of tumor-associated regulatory T cell biology. Trends Immunol. 2013 Jan; 34(1):33-40. PMID: 22999714.
      View in: PubMed
    16. Donkor MK, Sarkar A, Savage PA, Franklin RA, Johnson LK, Jungbluth AA, Allison JP, Li MO. T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-ß1 cytokine. Immunity. 2011 Jul 22; 35(1):123-34. PMID: 21757379.
      View in: PubMed
    17. Savage PA, Vosseller K, Kang C, Larimore K, Riedel E, Wojnoonski K, Jungbluth AA, Allison JP. Recognition of a ubiquitous self antigen by prostate cancer-infiltrating CD8+ T lymphocytes. Science. 2008 Jan 11; 319(5860):215-20. PMID: 18187659.
      View in: PubMed
    18. Smith NL, Savage PJ, Heckbert SR, Barzilay JI, Bittner VA, Kuller LH, Psaty BM. Glucose, blood pressure, and lipid control in older people with and without diabetes mellitus: the Cardiovascular Health Study. J Am Geriatr Soc. 2002 Mar; 50(3):416-23. PMID: 11943034.
      View in: PubMed
    19. Savage PA, Davis MM. A kinetic window constricts the T cell receptor repertoire in the thymus. Immunity. 2001 Mar; 14(3):243-52. PMID: 11290334.
      View in: PubMed
    20. Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, Johnson D, Swetter S, Thompson J, Greenberg PD, Roederer M, Davis MM. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med. 1999 Jun; 5(6):677-85. PMID: 10371507.
      View in: PubMed
    21. Savage PA, Boniface JJ, Davis MM. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity. 1999 Apr; 10(4):485-92. PMID: 10229191.
      View in: PubMed
    22. Yee C, Savage PA, Lee PP, Davis MM, Greenberg PD. Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J Immunol. 1999 Feb 15; 162(4):2227-34. PMID: 9973498.
      View in: PubMed
    23. Davis MM, Wülfing C, Krummel MF, Savage PA, Xu J, Sumen C, Dustin ML, Chien YH. Visualizing T-cell recognition. Cold Spring Harb Symp Quant Biol. 1999; 64:243-51. PMID: 11232292.
      View in: PubMed
    24. Archer SL, Liu K, Dyer AR, Ruth KJ, Jacobs DR, Van Horn L, Hilner JE, Savage PJ. Relationship between changes in dietary sucrose and high density lipoprotein cholesterol: the CARDIA study. Coronary Artery Risk Development in Young Adults. Ann Epidemiol. 1998 Oct; 8(7):433-8. PMID: 9738689.
      View in: PubMed
    25. Howard BV, Zech L, Davis M, Bennion LJ, Savage PJ, Nagulesparan M, Bilheimer D, Bennett PH, Grundy SM. Studied of very low density lipoprotein triglyceride metabolism in an obese population with low plasma lipids: lack of influence of body weight or plasma insulin. J Lipid Res. 1980 Nov; 21(8):1032-41. PMID: 7007543.
      View in: PubMed
    26. Howard BV, Savage PJ, Nagulesparan M, Bennion LJ, Davis M, Bennett PH. Changes in plasma lipoproteins accompanying diet therapy in obese diabetics. Atherosclerosis. 1979 Aug; 33(4):445-56. PMID: 228683.
      View in: PubMed
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