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.
Memorial Sloan-Kettering Cancer Center
New York, NY
- Cancer Immunology
University of California Berkeley
- Cancer Immunology
Stanford University School of Medicine
PhD - Cancer Biology
University of Virginia
BA - Biochemistry
Regulatory T Cell Development.
Savage PA, Klawon DEJ, Miller CH. Regulatory T Cell Development. Annu Rev Immunol. 2020 Jan 28.
Negligible Role for Deletion Mediated by cDC1 in CD8+ T Cell Tolerance.
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 05 01; 202(9):2628-2635.
Unlocking the Complexities of Tumor-Associated Regulatory T Cells.
Chao JL, Savage PA. Unlocking the Complexities of Tumor-Associated Regulatory T Cells. J Immunol. 2018 01 15; 200(2):415-421.
Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen.
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.
Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage.
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.
Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells.
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.
Close Encounters of the Tertiary Kind.
Lee V, Savage PA. Close Encounters of the Tertiary Kind. Immunity. 2015 Sep 15; 43(3):418-20.
Ablation of B7-H3 but Not B7-H4 Results in Highly Increased Tumor Burden in a Murine Model of Spontaneous Prostate Cancer.
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.
PD-1 regulates extrathymic regulatory T-cell differentiation.
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.
Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease.
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.
Young Investigator Award
Cancer Research Foundation
2010 - 2011
Cancer Research Institute
2010 - 2012
Damon Runyon Cancer Research Fund
2001 - 2004