Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses

Therapeutic efficacy of a tumor cell-based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechani sms that control autoreactive T cell responses: the cytotoxic T lymphocyte- associated antigen (CTLA)-4 pathway or the CD25(+) regulatory T (Treg) cell s. Combination of CTLA-4 blockade and depletion of CD25(+) Treg cells resul ts in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the freq uency of tyrosinase-related protein 2(180-188)-specific CTLs detected in th e periphery. Furthermore, tumor rejection is dependent on the CD8(+) T cell subset. Our data demonstrate that the CTL response against melanoma antige ns is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with im munoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25(+) Treg cells indicates that CD25(+) Treg cells and C TLA-4 signaling represent two alternative pathways for suppression of autor eactive T cell immunity. Simultaneous intervention with both regulatory mec hanisms is therefore a promising concept for the induction of therapeutic a ntitumor immunity.