Our goal is to explore strategies aimed at understanding and overcoming T cell tolerance as a way to improve adoptive immunotherapy for cancer and chronic viral infections. CD8+ T lymphocytes represent a branch of the immune system responsible for recognizing and destroying cancerous or infected cells. Adoptive T cell immunotherapy strives to harness this ability for the treatment of human disease by transferring large numbers of reactive T cells into patients. However, the anticipated clinical benefits of this treatment have not been realized for a majority of patients, highlighting the need for novel therapeutic approaches. Several obstacles to success have been identified including deletion and induction of tolerance in transferred T cells, as tumor antigens are often aberrantly or over-expressed self-antigens protected by mechanisms of peripheral self- tolerance. The tumor microenvironment also promotes the induction of tolerance by failing to provide appropriate co-stimulatory signals to T cells. Additionally, tolerance can be induced during chronic viral infections due to persistent over-stimulation (exhaustion), leading to expression of negative regulatory molecules that impair T cell receptor (TCR) signaling. Thus, while essential for protection against autoimmunity, tolerance represents a substantial challenge to mounting an effective CD8+ T cell immune response. Despite advances in T cell biology and tumor immunology, the molecular mechanisms that regulate tolerance remain largely unknown, hampering efforts to overcome in vivo tolerance for therapeutic applications. Recently, induced expression of genetically engineered TCR (dual-TCR) on transferred T cells has gained enthusiasm as a means to direct immune responses toward malignant or infected cells. These dual-TCR T cells have shown promise not only as cellular reagents for therapy, but also as tools to more effectively interrogate the mechanisms responsible for tolerance induction, which is regulated at least in part by proximal defects at independently functioning TCR complexes rather than global cellular defects. Experiments designed to understand at the molecular level how dually expressed TCR influence one another and direct T cell activity may provide key insight into how enduring therapeutic responses might be achieved in patients. The long-term objectives of this research are to evaluate strategies that exploit dual-TCR expression as means to rescue T cell tolerance, enhance the efficacy and durability of adoptively transferred T cells against established diseases, and to utilize such cells to explore the intracellular events that control induction of T cell tolerance.
The specific aims are (1) to rescue tumor-reactive CD8+ T cells tolerized during adoptive immunotherapy;(2) to elucidate the molecular mechanisms that regulate induction of CD8+ T cell tolerance;and (3) to restore function of exhausted CD8+ T cells during chronic viral infection. These experiments are designed to examine new avenues of immunotherapy and provide mechanistic insight into T cell tolerance and rescue such that these approaches may be translated to a broad range of human malignancies and infections.

Public Health Relevance

Adoptive T cell immunotherapy has shown promise as a therapy against cancer and chronic viral infections, but significant obstacles to clinical success remain. One of the primary challenges is maintaining survival and effectiveness of transferred T cells, which are often rendered tolerant or deleted following infusion into patients. We will explore strategies to periodically immunize and rescue adoptively transferred T cell populations to achieve durable therapeutic responses against tumor and virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI087764-04
Application #
8416940
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$343,159
Indirect Cost
$110,509
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Berrien-Elliott, Melissa M; Yuan, Jinyun; Swier, Lauryn E et al. (2015) Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells. Cancer Immunol Res 3:116-24
Jackson, Stephanie R; Berrien-Elliott, Melissa; Yuan, Jinyun et al. (2014) Neuropilin-1 expression is induced on tolerant self-reactive CD8+ T cells but is dispensable for the tolerant phenotype. PLoS One 9:e110707
Jackson, Stephanie R; Yuan, Jinyun; Berrien-Elliott, Melissa M et al. (2014) Inflammation programs self-reactive CD8+ T cells to acquire T-box-mediated effector function but does not prevent deletional tolerance. J Leukoc Biol 96:397-410
Jackson, Stephanie R; Yuan, Jinyun; Teague, Ryan M (2014) Targeting CD8+ T-cell tolerance for cancer immunotherapy. Immunotherapy 6:833-52
Jackson, Stephanie R; Berrien-Elliott, Melissa M; Meyer, Jennifer M et al. (2013) CD8+ T cell exhaustion during persistent viral infection is regulated independently of the virus-specific T cell receptor. Immunol Invest 42:204-20
Teague, Ryan M; Kline, Justin (2013) Immune evasion in acute myeloid leukemia: current concepts and future directions. J Immunother Cancer 1:
Berrien-Elliott, Melissa M; Jackson, Stephanie R; Meyer, Jennifer M et al. (2013) Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance. Cancer Res 73:605-16