TIM3 comes of age as an inhibitory receptor

Abstract

T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a member of the TIM family, was originally identified as a receptor expressed on interferon-γ-producing CD4 + and CD8 + T cells. Initial data indicated that TIM3 functioned as a ‘co-inhibitory’ or ‘checkpoint’ receptor, but due to the lack of a definable inhibitory signalling motif, it was also suggested that TIM3 might act as a co-stimulatory receptor. Recent studies have shown that TIM3 is part of a module that contains multiple co-inhibitory receptors (checkpoint receptors), which are co-expressed and co-regulated on dysfunctional or ‘exhausted’ T cells in chronic viral infections and cancer. Furthermore, co-blockade of TIM3 and programmed cell death 1 (PD1) can result in tumour regression in preclinical models and can improve anticancer T cell responses in patients with advanced cancers. Here, we highlight the developments in understanding TIM3 biology, including novel ligand identification and the discovery of loss-of-function mutations associated with human disease. In addition, we summarize emerging data from human clinical trials showing that TIM3 indeed acts as a ‘checkpoint’ receptor and that inhibition of TIM3 enhances the antitumour effect of PD1 blockade. The co-inhibitory receptor TIM3 can serve as a marker of exhausted T cells. Here, the authors investigate the biology of TIM3, discussing its various ligands, signalling pathways and association with human disease. They also provide an overview of emerging clinical data regarding its potential as an anticancer target in combination with PD1 blockade.