Prostate cancer is the most commonly diagnosed malignancy in American men, resulting in over 30,000 deaths annually. This high rate of mortality results mainly from the inability of standard therapies to effectively treat the metastatic form of the disease. Immune-based therapies represent a promising new approach to treating prostate cancer in part because the possible development of autoimmunity against non-malignant tissue (a potential side effect for most immune-based therapies) would not be problematic because the prostate is a non-essential organ. Several parameters can influence the efficacy of T cell-based therapies to treat cancer, one of the most critical being the development of tolerance towards the targeted tumor-antigens. To study the relationship between prostate cancer and T cell tolerance, we have developed a novel transgenic mouse system in which we can examine the functional status of a clonotypic population of CD4 cells specific for a prostate epithelial antigen in a variety of settings: 1) in the absence of disease, 2) during the development of prostate cancer, and 3) following androgen-ablation (a standard treatment for prostate cancer). Our preliminary data indicates that while prostate epithelial-specific CD4 cells are normally ignorant of their cognate antigen, the development of advanced prostate cancer converts this passive form of tolerance into a more active one in which these T cells are rendered functionally non-responsive. Interestingly, androgen-ablation mitigates the tolerogenic potential of prostate tumors, presumably by reducing the overall levels of tolerogenic antigen presentation, and potentially creating a therapeutic window during which tolerance might be less of an impediment towards tumor immunity. In this proposal we will investigate in more detail the relationship between prostate tumorigenesis and T cell tolerance by determining the disease stage at which tolerance develops, as well as the mechanisms by which tolerance is induced. Furthermore, we will apply this knowledge to the design of vaccine strategies to treat prostate cancer in a variety of therapeutic settings (including following androgen-ablation).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109339-04
Application #
7256935
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
2004-09-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$281,848
Indirect Cost
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Mittal, Payal; Abblett, Rebecca; Ryan, Joseph M et al. (2018) An Immunotherapeutic CD137 Agonist Releases Eomesodermin from ThPOK Repression in CD4 T Cells. J Immunol 200:1513-1526
Ryan, Joseph M; Mittal, Payal; Menoret, Antoine et al. (2018) A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice. Cancer Immunol Immunother 67:605-613
Adler, Adam J; Mittal, Payal; Ryan, Joseph M et al. (2017) Cytokines and metabolic factors regulate tumoricidal T-cell function during cancer immunotherapy. Immunotherapy 9:71-82
Ryan, Joseph M; Wasser, Jeffrey S; Adler, Adam J et al. (2016) Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too? Expert Opin Biol Ther 16:655-74
Tsurutani, Naomi; Mittal, Payal; St Rose, Marie-Clare et al. (2016) Costimulation Endows Immunotherapeutic CD8 T Cells with IL-36 Responsiveness during Aerobic Glycolysis. J Immunol 196:124-34
Mittal, Payal; St Rose, Marie-Clare; Wang, Xi et al. (2015) Tumor-Unrelated CD4 T Cell Help Augments CD134 plus CD137 Dual Costimulation Tumor Therapy. J Immunol 195:5816-26
Adler, Adam J; Vella, Anthony T (2013) Striving for synergy: how to improve cancer immunotherapy through multiple agonist costimulation. Immunotherapy 5:1271-3
Adler, Adam J; Vella, Anthony T (2013) Betting on improved cancer immunotherapy by doubling down on CD134 and CD137 co-stimulation. Oncoimmunology 2:e22837
St Rose, Marie-Clare; Taylor, Roslyn A; Bandyopadhyay, Suman et al. (2013) CD134/CD137 dual costimulation-elicited IFN-? maximizes effector T-cell function but limits Treg expansion. Immunol Cell Biol 91:173-83
Ngoi, Soo Mun; St Rose, Marie-Clare; Menoret, Antoine M et al. (2012) Presensitizing with a Toll-like receptor 3 ligand impairs CD8 T-cell effector differentiation and IL-33 responsiveness. Proc Natl Acad Sci U S A 109:10486-91

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