Ryan Teague, Ph.D.
Molecular Microbiology and Immunology
Immunotherapy relies on tumor-specific T cells to target and eradicate cancer cells, and this potential has motivated immunologists and oncologists for many decades. Despite tremendous recent success, translating immunotherapy into a reliable treatment option for most cancer patients is still not a reality. One of the major challenges to successful immunotherapy is the induction of T cell tolerance within patients. Tolerance is multifaceted, involving both the death of tumor-reactive T cells and the induction of anergy, which renders any surviving T cells inert. Research in our lab aims to identify and therapeutically target the molecular mechanisms that regulate T cell tolerance as a means to boost anti-tumor immunity, and ultimately to inform translational efforts to provide enhanced immunotherapy for patients with cancer.
Targeting mechanisms of T cell dysfunction for immunotherapy: Work from our lab has demonstrated that T cell tolerance can be overcome to elicit durable immunotherapy in mice with disseminated leukemia by administrating antibodies that block T cell co-inhibitory checkpoint molecules such as PD-1, CTLA-4 and LAG-3. Similar “checkpoint blockade” approaches are now being tested in human clinical trials, but the molecular mechanisms required to rescue T cell function have not been clearly identified. This hampers efforts to improve outcomes in a broader range of cancer patients. We recently discovered that activation of the transcription factor T-bet is required to reinvigorate tumor-infiltrating CD8+ T cells for successful checkpoint blockade immunotherapy. Our ongoing studies are aimed at identifying the genes targeted by T-bet during this complex process, and uncovering additional cellular and molecular mechanisms involved.
Obesity as an obstacle to cancer immunotherapy: Nearly 35% of Americans are obese, and this is expected to rise in the next decade. The link between obesity and increased prevalence of cancer has been established in humans and likely stems in part from loss of vigilant innate and adaptive immune surveillance. However, the mechanisms that undermine tumor immunity in obese patients are largely unknown. Recent studies in our lab have revealed poor anti-tumor immunity in obese mice treated with checkpoint blockade immunotherapy. Our ongoing research is aimed at determining how poor diet and obesity influence cell-mediated immunity toward cancer, and to identify translational strategies to overcome the challenges of obesity for enhanced immunotherapy and better outcomes in a larger number of patients.
Diversity of tumor-infiltrating T cells: A hallmark of aging in both mice and humans is involution of the thymus, which greatly reduces the output of new T cells later in life. An intriguing aspect of this gradual process is the accumulation of adipose (fat) tissue in the thymus, which is exacerbated in obese mice that experience accelerated thymic involution. The subsequent loss of T cells renders older individuals more susceptible to infection and less responsive to immune modulation efforts like vaccination. We predict this is also true for obese individuals but at a much younger age. How changes in thymic output impact immunotherapy and the diversity of T cells that infiltrate tumors in obese individuals is unknown. We are using next-generation DNA sequencing to define the diversity of thousands or even millions of T cells within a progressing tumor. This technology allows us to quantify unique T cell receptor sequences and accurately measure the richness of a heterogeneous T cell population from select tissues and tumors, and determine if this is altered during immunotherapy.
Labs and Facilities
Lab team members are Simone Geraud, Lindsey Kuehm, Ryan Teague, Lauryn Klevorn and Nicole McLaughlin.
Teaching old CAR-T cells new tricks.
Lindsey M Kuehm and Ryan M. Teague
Journal of Leukocyte Biology (102):188-190 (2017)
Pubmed Abstract Link: 28765509
Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.
Lauryn E. Klevorn, Melissa M. Berrien-Elliott, Jinyun Yuan, Lindsey M. Kuehm, Gregory D. Felock, Sean A. Crowe, and Ryan M. Teague.
Cancer Immunology Research, 2016 (12):1016-26.
Pubmed Abstract Link: 27803062
BTLA and HVEM govern induction of extrathymic regulatory T cells and tolerance by
Andrew Jones, Jessica Bourque, Lindsey Kuehm, Adeleye Opejin, Ryan M. Teague, Cindy Gross and Daniel Hawiger.
Immunity, 2016 (5):1066-1077.
Pubmed Abstract Link: 27793593
Adapting Cancer Immunotherapy Models for the Real World.
Lauryn E. Klevorn and Ryan M. Teague.
Trends in Immunology, 2016 37(6):354-363.
Pubmed Abstract Link: 27105824
Checkpoint Blockade Immunotherapy Relies on T-bet but Not Eomes to Induce Effector
Function in Tumor-Infiltrating CD8+ T Cells. Berrien-Elliott MM, Yuan J, Swier LE,
Jackson SR, Chen CL, Donlin MJ, Teague RM.
Cancer Immunology Research, 2015 3(2):116-124.
Pubmed Abstract Link: 25516478
Neuropilin-1 Expression Is Induced on Tolerant Self-Reactive CD8+ T Cells but Is Dispensable
for the Tolerant Phenotype.
Jackson SR, Berrien-Elliott M, Yuan J, Hsueh EC, Teague RM.
PLoS One, 2014 Oct 24;9(10):e110707.
Pubmed Abstract Link: 25343644
Targeting CD8(+) T-cell tolerance for cancer immunotherapy.
Jackson SR, Yuan J, Teague RM.
Immunotherapy, 2014 Jul;6(7):833-52.
Pubmed Abstract Link: 25290416
In vitro induced regulatory T cells are unique from endogenous regulatory T cells
and effective at suppressing late stages of ongoing autoimmunity.
Nguyen TL, Makhlouf NT, Anthony BA, Teague RM, DiPaolo RJ.
PLoS One, 2014 Aug 13;9(8):e104698.
Pubmed Abstract Link: 25119105
Inflammation programs self-reactive CD8+ T cells to acquire T-box-mediated effector
function but does not prevent deletional tolerance.
Stephanie R. Jackson, Jinyun Yuan, Melissa M. Berrien-Elliot, Collin L. Chen, Jennifer M. Meyer, Maureen J. Donlin, Ryan M. Teague
J Leukoc Biol, 2014 Sep;96(3):397-410. doi: 10.1189/jlb.1A0913-500RR.
Pubmed Abstract Link: 24823810
Immune evasion in acute myeloid leukemia: Current concepts and future directions.
Ryan M. Teague and Justin Kline.
Journal for Immunotherapy of Cancer, 2013 1:13.
Pubmed Abstract Link: 24353898
CD40 ligation reverses T cell tolerance in acute myelid leukemia.
Long Zhang, Xiao Liu, Xiufen Chen, Ryan M. Teague, Thomas F. Gajewski, and Justin Kline.
Journal of Clinical Investigation, 2013 123:1999-2010.
Pubmed Abstract Link: 23619361
CD8+ T cell exhaustion during persistent viral infection is regulated independently
of the virus-specific T cell receptor.
Stephanie R. Jackson, Melissa M. Berrien-Elliott, Jennifer M. Meyer, E. John Wherry, and Ryan M. Teague.
Immunological Investigations, 2013 42:204-220.
Pubmed Abstract Link: 23461613
Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory
pathways of CD8+ T-cell tolerance.
Berrien-Elliott MM, Jackson SR, Meyer JM, Rouskey CJ, Nguyen TL, Yagita H, Greenberg P, DiPaolo RJ, and Teague RM.
Cancer Research, 2013 73:605-16.
Pubmed Abstract Link: 23188506
Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T
Teague RM, Greenberg PD, Fowler C, Huang MZ, Tan X, Morimoto J, Dossett ML, Huseby ES, Ohlén C.
Immunity, 2008 May;28(5):662-74.
Pubmed Abstract Link: 18424189
Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of
Teague RM, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan X, Sutton SE, Cooke MP, Ohlén C, Greenberg PD.
Nature Medicine, 2006 Mar;12(3):335-41.
Pubmed Abstract Link: 16474399