Immunotherapy Targeting 4-1BB and Its Ligand

Abstract

T-cell activation in the absence of costimulation is futile because T-cells deprived of costimulatory signals enter a state of unresponsiveness or anergy. The interaction of 4-1BB and 4-1BB ligand (4-1BBL) activates an important costimulatory pathway with diverse and important roles in immune regulation. Signals relayed through 4-1BB generate strong CD8(+) T-cell responses rather than CD4(+) T-cell responses; this action results in cytokine induction and promotes T-cell survival. In recent years, 4-1BB-mediated immune regulation has gained great significance because of the seemingly contradictory dual roles of agonistic anti-4-1BB in vivo disease models. To date, agonistic 4-1BB monoclonal antibody has shown therapeutic potential against a variety of tumors, CD4(+) T-cell-mediated autoimmune diseases, and chronic graft-versus-host disease. In addition, blockade of 4-1BB/4-1BBL interaction has produced therapeutic effects against coxsackievirus-induced myocardial inflammation, herpetic stromal keratitis, and graft rejection. We propose that the dual roles of agonistic anti-4-1BB--an enhanced effector function and a suppressor function--are mediated by a novel CD11c(+)CD8(+) T-cell population.