T-cell immunoglobulin domain and mucin domain-3 (TIM-3) is increasingly considered to be an important target in cancer immunotherapy given its important role in immune tolerance and induction of T cell exhaustion in chronic viral infection and cancer. However, a challenge for the community has been that although TIM-3 inhibits T cell responses, it also sometimes activates, making targeting TIM-3 potentially challenging. A study led by Richard S. Blumberg, MD, BWH Department of Medicine, with the group of Vijay Kuchroo, DVM, PhD, of the Center for Neurologic Disease, has discovered that the ability of TIM-3 to mediate tolerance is dependent upon the protein carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another activation antigen on T cells that has inhibitory properties.
In the current study, these investigators show that CEACAM1 is an important binding partner for TIM-3. Critical to the interactions between CEACAM1 and TIM-3 is the highly related amino terminal, membrane distal immunoglobulin V-like domains of either protein, as shown by biochemical, biophysical and X-ray crystallography studies. CEACAM1 is required for the inhibitory function, full maturation and cell surface expression of TIM-3. CEACAM1 deficient T cells are hyper-inflammatory and have decreased cell-surface TIM-3 expression and regulatory cytokines, which are restored by CEACAM1 expression in T cells. CEACAM1 and TIM-3 are expressed in exhausted T cells during chronic viral infection and cancer. Finally, blocking both CEACAM1 and TIM-3 enhances anti-tumor immune responses and tumor elimination in preclinical models of colon.
“CEACAM1 functions as a novel heterophilic ligand for TIM-3 and is necessary for TIM-3-mediated tolerance which has marked consequences for inflammation