Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo

The OX-40 receptor (OX-40R) is a member of the tumor necrosis factor recept or (TNF-R) superfamily that is expressed on activated CD4(+) T cells. The O X-40R is a costimulatory molecule that induces CD4(+) T cell activation whe n engaged by its ligand (OX-40 L; found on antigen presenting cells). In hu man and murine tumors, we have shown upregulation of the OX-40R on CD4(+) T cells from tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph n ode cells (TDLNC) but not on systemic CD4(+) T cells, such as peripheral bl ood lymphocytes (PBL) or splenocytes. In order to examine potentially heigh tened anti-tumor immunity through enhanced costimulation when engaging OX-4 0R in vivo, we inoculated mice with a murine mammary cancer cell line (SM1) and then treated with a soluble form of the OX-40 L. Mice injected with a lethal inoculum of SM1 cells were given two intraperitoneal injections (day s 3 and 7 post-inoculation) of 100 mug soluble OX-40 L. Seven of 28 treated mice survived the lethal tumor inoculum, as compared to one of 28 control mice, demonstrating a significant survival benefit with treatment (p = 0.01 36, log rank analysis). Mice that did not develop tumor by day 90 were rech allenged; all remained tumor-free. Mice were also injected with a second ma mmary tumor line (4T1) and treated with OX-40 L:Ig with similar therapeutic results. Activation of OX-40R(+) CD4(+) T cells during mammary cancer prim ing stimulated an anti-tumor immune response resulting in enhanced survival and protective anti-tumor immunity. These results should have practical ap plications for treatment modalities for patients with breast cancer.