Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells (dendritic cells, NK cells, monocytes).
HAVCR2 belongs to TIM family cell surface receptor proteins. These proteins share a similar structure, in which the extracellular region consists of membrane distal single variable immunoglobulin domain (IgV) and a glycosylated mucin domain of variable length located closer to the membrane. Intracellular domain of HAVCR2 is called C-terminal cytoplasmic tail. It contains five conserved tyrosine residues that interact with multiple components of T-cell receptor (TCR) complex and negatively regulates its function.
HAVCR2 is primarily activated by galectin-9. The engagement leads to stimulation of an influx of calcium to intracellular space and induction of programmed cell death, apoptosis. As a consequence, a suppression of Th1 and Th17 responses and induction of immune tolerance occurs. In addition to galectin-9, a couple other ligands have been identified, such as phospatidyl serine (PtdSer), High Mobility Group Protein 1 (HMGB1) and Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1). The binding of PtdSer has been shown to cause an uptake of apoptotic cells and reduced cross presentation of dying cell-associated antigens by dendritic cells. The binding of HMGB1 can interfere with nucleic acid stimulation and suppresses activation of innate immune response. The role of CEACAM1 engagement is still not clear.
The HAVCR2 pathway may interact with the PD-1 pathway in the dysfunctional CD8+ T cells and Tregs in cancer. HAVCR2 is mainly expressed on activated CD8+ T cells and suppresses macrophage activation following PD-1 inhibition. Upregulation was observed in tumors progressing after anti-PD-1 therapy. This seems to be a form of adaptive resistance to immunotherapy. Multiple phase 1/2 clinical trials with anti-HAVCR2 monoclonal antibodies (LY3321367, Eli Lilly and Company; MBG453, Novartis Pharmaceuticals; TSR-022, Tesaro, Inc.) in combination with anti-PD-1 or anti-PD-L1 therapies are ongoing.
The role of HAVCR2 in the T-cell dysfunction has been investigated in chronic viral infections.
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^Clinical trial number NCT03099109 for "A Study of LY3321367 Alone or With LY3300054 in Participants With Advanced Relapsed/Refractory Solid Tumors" at ClinicalTrials.gov
^Clinical trial number NCT02608268 for "Safety and Efficacy of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies" at ClinicalTrials.gov
^Clinical trial number NCT02817633 for "Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors" at ClinicalTrials.gov