CTLA-4 BLOCKADE SYNERGIZES WITH TUMOR-DERIVED GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR FOR TREATMENT OF AN EXPERIMENTAL MAMMARY-CARCINOMA

Generation of a T cell-mediated antitumor response depends on T cell r eceptor engagement by major histocompatibility complex/antigen as well as CD28 ligation by B7, CTLA-4 is a second B7 receptor expressed by T cells upon activation that, unlike CD28, appears to deliver an inhibi tory signal to T cells. Recently, we and others demonstrated that admi nistration of an anti-CTLA-4 antibody was sufficient to promote regres sion of several murine tumors. However, certain tumors, such as the SM 1 mammary carcinoma, remain refractory to this type of immunotherapy, In the present study, we report that the combination of both CTLA-4 bl ockade and a vaccine consisting of granulocyte-macrophage colony-stimu lating factor-expressing SMI cells resulted in regression of parental SM1 tumors, despite the ineffectiveness of either treatment alone. Thi s synergistic therapy resulted in long-lasting immunity to SM1 and dep ended on both CD4(+) and CD8(+) T cells. Interestingly, synergy was no t observed between CTLA-4 and a B7-expressing SM1 vaccine. Given that granulocyte-macrophage colony-stimulating factor promotes differentiat ion and activation of dendritic cells as well as enhances cross-primin g of T cells to tumor-derived antigens and that SM1 is major histocomp atibility complex class II-negative, our findings suggest that CTLA-4 blockade acts at the level of a host-derived antigen-presenting cell. In addition, these results also support the idea that the most effecti ve and synergistic vaccine strategy targets treatments that enhance T cell priming at the level of host-derived antigen-presenting cells.