Ryan Teague, Ph.D.
Ryan Teague, Ph.D.
Fred Hutchinson Cancer Research Center, 2002-2008
Doisy Research Center
Ryan Teague, Ph.D.
Introduction: T lymphocytes (T cells) represent a major arm of the immune system responsible for recognizing and eliminating cancer and infected cells. The ability of T cells to mediate anti-tumor effects in people is well documented, but harnessing this activity to provide a reliable therapeutic benefit has been challenging. The strategies for engaging T cell-mediated anti-tumor activity involve activating T cells through vaccination, or adoptively transferring tumor-reactive T cells following isolation and expansion in vitro. Many obstacles to success with these strategies have been identified, including selecting an appropriate tumor antigen to target, maintaining the response in the context of persistent antigen stimulation, and overcoming inhibitory and tolerizing pathways resulting from the tumor and the nature of the antigen being targeted. The research in my lab is aimed at understanding the immune response to tumors, with particular interest in leukemia, lymphoma, breast, and prostate cancer. Our goal is to engineer animal models and design experiments that allow us to address the issues relevant to the clinical translation of T cell-based immunotherapy for treatment of human cancer.
Project 1: Exploiting dual T cell receptors for rescue of anti-tumor CD8+ T cells
One of the primary reasons for failure of immunotherapy is the challenge of maintaining survival and efficacy of infused T cells, which are often deleted after infusion but before any beneficial anti-tumor/viral activity can be exacted. Our previous work demonstrated that expression of peripheral self-antigen is largely responsible for such deletion in mice, and that any T cells remaining from the deleted population are rendered tolerant; failing to expand upon subsequent antigen stimulation (Morimoto et al, J. Immunol. 2007). Thus, understanding how to prevent or overcome deletion and induction of tolerance in adoptively transferred CD8+ T cells could lead to improved outcomes for patients being treated for cancer or chronic viral infection. To this end, we recently showed that expression of a second T cell receptor (TCR) specific for a foreign protein (i.e. not a self/tumor-antigen) provided a means to expand and rescue function of tolerant CD8+ T cells in vivo (Teague et al, Immunity 2008). Such dual-TCR T cells could be expanded periodically via immunization through the second non-tolerized TCR by infusion of antigen presenting cells (APC) pulsed with appropriate peptide, and these rescued T cells provided resistance to subsequent challenge with live leukemic tumor. Although this work provided key insights into the fate of infused CD8+ T cells and the mechanisms that regulate induction and maintenance of CD8+ T cell tolerance, it did not specifically address the issues of preventing deletion or rescuing T cells for treatment of cancer. Thus, we are now exploring this strategy as a potential improvement to T cell-based immunotherapy by immunizing dual-TCR T cells in vivo via a second expressed receptor to maintain population size and effector function following adoptive transfer into leukemia-bearing recipients. We have also begun utilizing similar approaches to examine the utility of dual-TCR T cells for the treatment of chronic viral infections.
Project 2:Attenuating negative regulatory pathways for adoptive T cell immunotherapy of cancer
T cell-based adoptive immunotherapy for cancer requires that tumor-reactive CD8+ T cells survive and be present in sufficient numbers to overcome progressive malignancy, but tolerizing influences within the host and tumor microenvironment often lead to deletion of transferred T cells, and inhibition of effector mechanisms. The inability to sustain infused T cells represents a substantial challenge to the success of adoptive immunotherapy, as the complex array of both positive and negative signals that dictate whether T cells survive, get deleted, or become tolerant are not well understood. Signals induced by ligation of the negative regulatory receptors CTLA4, PD-1 or LAG3 normally serve to hinder T cell responses through non-redundant biochemical processes that interfere with stimulatory pathways. Our lab has utilized an established mouse model of T cell tolerance to describe complimentary and distinct roles for these inhibitory receptors in regulating CD8+ T cell deletion and effector cell differentiation during cancer immunotherapy. Blocking CTLA4 and PD-1 in vivo combined to promote survival of transferred T cells despite powerful deletional signals that mediate Bim-dependent apoptosis. The additional blockade of LAG3 resulted in acquisition of cytolytic activity by these surviving T cells, and together these interventions provided durable immunotherapy for established and disseminated leukemia.
Future projects: Genetically engineering T cells to provide more durable immunotherapy for cancer
Several receptors expressed by T cells can impede their function, representing attractive targets for antibody blockade treatment. For example, the negative regulatory receptors CTLA-4, PD-1, LAG-3 and BTLA may all contribute in some regard to the functional defects associated with T cell tolerance. However, the various inhibitory mechanisms employed by these negative regulatory receptors remain enigmatic. Because they appear to have non-redundant inhibitory functions, our work has focused on combination blockade approaches that cooperate to rescue T cell tolerance for improved therapeutic outcomes.
In addition to negative regulatory receptor blockade, we have devised several potential strategies to overcome T cell tolerance using different vaccination techniques. Separately, we have performed gene array studies to generate unique insight into the early transcriptional events that influence CD8+ T cell tolerance. Together, these projects have identified a plethora of potential molecular targets likely involved in cell fate decisions (i.e. tolerance versus immunity. We have now acquired or engineered knockout mice, inhibitory shRNA expression systems, and recombinant viral vectors that allow the discrete manipulation of many of these pathways for experimental analysis. These projects are being designed to discover the molecular mechanisms that regulate tolerance in transferred T cells, to identify the pathways that may be exploited for T cell rescue, and to inform future efforts to deliver more durable immunotherapy to patients with cancer.
Left to right: Sindu Vellanki, Jen Meyer, Melissa Berrien, Ryan Teague, Jinyun Yuan, Stephanie Jackson, Collin Chen
Long Zhang, Xiao Liu, Xiufen Chen, Ryan M. Teague, Thomas F. Gajewski, and Justin Kline.
Intravenously disseminated acute myeloid leukemia promotes immune evasion through induction of T cell tolerance which is prevented by CD40 ligation.
Journal of Clinical Investigation (2013 - In press).
Stephanie R. Jackson, Melissa M. Berrien-Elliott, Jennifer M. Meyer, E. John Wherry, and Ryan M. Teague.
CD8+ T cell exhaustion during persistent viral infection is regulated independently of the virus-specific T cell receptor.
Immunological Investigations (2013 - In press).
Berrien-Elliott MM, Jackson SR, Meyer JM, Rouskey CJ, Nguyen TL, Yagita H, Greenberg P, DiPaolo RJ, and Teague RM.
Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance.
Cancer Research, 2013 73:605-16.
Pubmed Abstract Link: 23188506
Michelle L. Dossett, Ryan M. Teague, Thomas M. Schmitt, Xiaoxia Tan, Lawrence J. Cooper, Cristina Pinzon, and Philip D. Greenberg.
Adoptive immunotherapy of disseminated leukemia with TCR-transduced, CD8+ T cells expressing a known endogenous TCR.
Molecular Therapy, 2009 17:742-749 (2009).
Pubmed Abstract Link: 19209146
Teague RM, Greenberg PD, Fowler C, Huang MZ, Tan X, Morimoto J, Dossett ML, Huseby ES, Ohlén C. Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor.
Immunity. 2008 May;28(5):662-74.
Pubmed Abstract Link: 18424189
Morimoto J, Tan X, Teague RM, Ohlén C, Greenberg PD.
Induction of tolerance in CD8+ T cells to a transgenic autoantigen expressed in the liver does not require cross-presentation.
J Immunol. 2007 Jun 1;178(11):6849-60.
Pubmed Abstract Link: 17513733
Teague RM,, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan X,Sutton SE, Cooke MP, Ohlén C, Greenberg PD.
Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors.
Nat Med. 2006 Mar;12(3):335-41.
Pubmed Abstract Link: 16474399
Teague RM, Tempero RM, Thomas S, Murali-Krishna K, Nelson BH.
Proliferation and differentiation of CD8+ T cells in the absence of IL-2/15 receptor beta-chain expression or STAT5 activation.
J Immunol. 2004 Sep 1;173(5):3131-9.
Pubmed Abstract Link: 15322173
Teague RM, Harlan LM, Benedict SH, Chan MA.
MIP-1alpha induces differential MAP kinase activation and IkappaB gene expression in human B lymphocytes.
J Interferon Cytokine Res. 2004 Jul;24(7):403-10.
Pubmed Abstract Link: 15296651
Rumsey LM, Teague RM, Benedict SH, Chan MA. MIP-1alpha induces activation of phosphatidylinositol-3 kinase that associates with Pyk-2 and is necessary for B-cell migration.
Exp Cell Res. 2001 Aug 1;268(1):77-83.
Pubmed Abstract Link: 11461120
Omoike OI, Teague RM, Benedict SH, Chan MA. MIP-1alpha induces binding of nuclear factors to the kappaB DNA element in human B cells.
Mol Cell Biol Res Commun. 2000 Jul;4(1):15-9.
Pubmed Abstract Link: 11152622
McDonald JT, Teague RM, Benedict SH, Chan MA. Induction of PYK-2 phosphorylation during LFA-1/ICAM-1-dependent homotypic adhesion of fresh human B-cells.
Immunol Invest. 2000 Feb;29(1):71-80.
Pubmed Abstract Link: 10709848
Title: Exploiting dual-TCR for rescue of CD8+ T cell tolerance in adoptive immunotherapy
Role: Principal Investigator
Awarded: $1,250,000/5 years
Period: 02/01/2010 – 01/31/2015
Cancer Research Institute
Title: Overcoming obstacles for improved adoptive T cell immunotherapy
Role: Principal Investigator
Awarded: $200,000/4 years
Period: 07/01/2010 – 06/30/2014
Saint Louis University President's Research Fund
Title: Engineering a novel mouse model of prostate cancer immunotherapy
Role: Principal Investigator
Awarded: $25,000/1 year
Period: 02/01/2010 – 02/28/2011