Releasing the Brake: Targeting Cbl-b to Enhance Lymphocyte Effector Functions

Abstract

The E3 ubiquitin ligase Cbl-b is an established nonredundant negative regulator of T-cell activation. Cbl-b fine-tunes the activation threshold of T cells and uncouples T cells from their vital need of a costimulatory signal to mount a productive immune response. Accordingly, mice deficient incblbare prone to autoimmunity and reject tumors. The latter has been described to be mediatedviaCD8+T cells, which are hyperactive and more abundant in shrinking tumors ofcblb-deficient animals. This might at least also in part be mediated by resistance ofcblb-deficient T cells to negative cues exerted by tumor-associated immuno-suppressive factors, such as TGF-βand regulatory T cells (Treg). Experiments usingcblb-deficient T cells either alone or in combination with vaccines validate the therapeutic concept of enhancing the efficacy of adoptively transferred lymphocytes to treat malignant tumors. This paper summarizes the current knowledge about the negative regulatory role of Cbl-b in T-cell activation and its potential therapeutic implications for cancer immunotherapy.