5F7184868171285ENSG00000135077ENSMUSG00000020399Q8TDQ0Q8VIM0NM_032782NM_134250NP_116171NP_599011Hepatitis 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 HAVCR2 (TIM-3) gene.

[11] Similar to other checkpoint inhibitors such as PD-1 and CTLA-4, TIM-3 has been successfully targeted to treat several solid and hematogenous malignancies, including melanoma, AML, and MDS.

These proteins share a similar structure, in which the extracellular region consists of membrane distal single variable immunoglobulin domain (IgV), a glycosylated mucin domain of variable length located closer to the membrane [16] transmembrane region, and intracellular stem.

The IGV domain is form by two antiparallel beta sheets that are linked by disulfide bridges between four conserved cysteines.

It contains five conserved tyrosine residues that interact with multiple components of T-cell receptor (TCR) complex,[19][20] mediates intercellular signaling pathways and negatively regulates its function.

[22][23] Combined blockade of HAVCR2 and PD-1 led to improved CD8+ T-cell response during the lymphocytic choriomeningitis virus infection.

[26][17][18] As a consequence, a suppression of Th1 and Th17 responses and induction of immune tolerance occurs, gal-9/HAVCR2 increases the immunosuppressive activity of Treg cells.

[14] In addition to galectin-9, several ligands have been identified, such as phosphatidylserine (PtdSer),[27] High Mobility Group Protein 1 (HMGB1)[28] and Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1).

[14] HAVCR2 expression is up regulated in tumor-infiltrating lymphocytes in lung,[8] gastric,[30] head and neck cancer,[31] schwannoma,[32] melanoma[33] and follicular B-cell non-Hodgkin lymphoma.

Multiple phase 1/2 clinical trials with anti-HAVCR2 monoclonal antibodies (LY3321367,[38] Eli Lilly and Company; MBG453,[39] Novartis Pharmaceuticals; TSR-022,[40] Tesaro, Inc.) in combination with anti-PD-1 or anti-PD-L1 therapies are ongoing.

Blockade of this receptor can improve the NK cells antitumor activity in esophageal cancer, melanoma and lung adenocarcinoma.