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.
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