Engagement of the OX-40 receptor in vivo enhances antitumor immunity

The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expr essed on activated CD4(+) T lymphocytes. Engagement of the OX-40R, with eit her OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R(+) T cells isolated from inflammatory l esions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R(+) T cells within primary tumors and tumor-invaded lym ph nodes of patients with cancer and hypothesized that they are the tumor-A g-specific T cells. Therefore, we investigated whether engagement of the OX -40R in vivo during tumor priming would enhance a tumor-specific T cell res ponse. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming r esulted in a significant improvement in the percentage of tumor-free surviv ors (20-55%) in four different murine tumors derived from four separate tis sues. This anti-OX-40R effect was dose dependent and accentuated tumor-spec ific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repert oire of the host's tumor-specific CD4(+) T cells. The identification of OX- 40R(+) T cells clustered around human tumor cells in vivo suggests that eng agement of the OX-40R may be a practical approach for expanding tumor-react ive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.