Optimal antitumoral immunity arises from robust expansion of T cells activated in response to antigen-specific costimulation. Costimulation results from ligation of T cell CD28 by B7 ligand combined with TCR occupancy by cognate antigen/MHC. Underscoring the importance of this mechanism, it has been shown that selective potentiation of costimulation can enhance antitumoral T cell responses. Thus, manipulations capable of reducing T cell costimulatory activation thresholds might also prove useful to potentiate antitumoral responses during immunotherapeutic treatment. In this proposal, we demonstrate that androgen withdrawal systemically lowers T cell activation thresholds in post-pubertal male mice. We also show that androgen withdrawal markedly elevates T cell levels within peripheral lymphoid organs. Accompanying these changes, castrated mice display an increased ability to mount antigen/tissue-specific T cell responses following vaccination. Prompted by these novel observations, we hypothesize that appropriate manipulation of gonadal steroid hormone might prove useful to facilitate host T cell antitumoral responses to immunotherapy. To test this, we will examine the potential of androgen withdrawal to facilitate T cell responses prior to and during antitumoral immunotherapeutic treatment. Our study encompasses the following Specific Aims: I. Test whether androgen deprivation promotes T cell acquisition of effector function in a defined-antigen, transgenic-TCR system; II. Establish the mechanism whereby androgen deprivation lowers T cell activation thresholds; Ill. Test whether clinical androgen deprivation reduces T cell activation thresholds in prostate cancer patients; and IV. Test whether androgen deprivation can improve responses to antitumoral immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA105138-01
Application #
6720478
Study Section
Special Emphasis Panel (ZRG1-ET-1 (04))
Program Officer
Yovandich, Jason L
Project Start
2004-09-17
Project End
2009-08-31
Budget Start
2004-09-17
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$302,375
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Thompson, R Houston; Kwon, Eugene D; Allison, James P (2009) Inhibitors of B7-CD28 costimulation in urologic malignancies. Immunotherapy 1:129-39
Inman, Brant A; Davies, Judson D; Rangel, Laureano J et al. (2008) Long-term outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostate-specific antigen level >or =50 ng/mL. Cancer 113:1544-51
Roth, Timothy J; Sheinin, Yuri; Lohse, Christine M et al. (2007) B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy. Cancer Res 67:7893-900
Blocki, Frank A; Radhakrishnan, Suresh; Van Keulen, Virginia P et al. (2006) Induction of a gene expression program in dendritic cells with a cross-linking IgM antibody to the co-stimulatory molecule B7-DC. FASEB J 20:2408-10