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

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.