Wolf et al. reviewed the growing body of evidence that TIM3, with multiple ligands and no known negative signaling motifs, is a negative co-regulator that serves to limit IFNγ-driven inflammation and enhance the effect of PD-1 blockade. On CD4+ and CD8+ T cells, TIM3 is co-expressed with PD-1 and is present on the most highly dysfunctional CD8+PD-1+ TILs and the most suppressive, predominant Treg cells in tumors. Co-blockade of PD-1 and TIM3 in mouse tumor models was synergistic compared with PD-1 blockade alone. Although the mechanism of action is unclear, anti-TIM3/PD-1 combinations are being tested in numerous early-stage human trials.
Contributed by Katherine Turner
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-gamma-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.
Author Info: (1) Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Brigham and Women'
Author Info: (1) Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (2) Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (3) Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. vkuchroo@evergrande.hms.harvard.edu. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. vkuchroo@evergrande.hms.harvard.edu.
