Mice injected with agonist anti-OX40 antibody remain tumor-free after injection with cancer cells.

Regulatory T (T reg) cells prevent autoimmunity by keeping self-reactive effector T cells in check, but this suppression becomes counterproductive when the effector cells are prevented from attacking tumors. Piconese et al. now show on page 825, however, that tumor immunity can be achieved without risking autoimmunity simply by stimulating a T cell surface protein called OX40.

A major challenge in tumor immunotherapy lies in breaking T reg cell–mediated tumor tolerance without inducing organism-wide autoimmunity or compromising immune surveillance. This goal has remained elusive because current methods used to derail T reg cell activity—such as depleting them using antibodies to a major T reg cell surface marker, CD25—also target effector T cells, thereby preventing tumor immunity and perhaps immunity to pathogens. T reg cell depletion also provokes conversion of effector T cells into T reg cells, thus worsening the initial immune suppression.

Piconese et al. sought a different approach by targeting OX40 because its stimulation suppresses T reg cell function while enhancing effector T cell survival and activity in vitro. Mice injected with agonistic anti-OX40 antibody before their injection with a carcinoma cell line efficiently rejected the tumor. Anti-OX40 injection also melted established tumors and promoted lasting immunity against the cancer.

Suppression of T reg cells in the tumor enhanced the migration of tumor-infiltrating dendritic cells (DCs) and allowed the DCs to carry tumor antigens to the draining lymph node, where they could then activate a new wave of tumor-reactive T cells. Meanwhile, the triggering of OX40 on effector T cells also enhanced tumor immunity, thus providing a double benefit. Mice injected twice with anti-OX40 antibody showed no evidence of autoimmunity and no change in T reg cell number, so OX40 may be a promising target for cancer immunotherapy.