HAVCR2

In a screen to identify differentially expressed molecules between Th1 and Th2 cells, Vijay Kuchroo and colleagues first described HAVCR2/TIM-3 in 2002. Kuchroo was the first to characterize the inhibitory function of TIM-3 and its role in inhibiting T cell responses in both autoimmunity and cancer.{{cite journal | vauthors = Kuchroo VK, Meyers JH, Umetsu DT, DeKruyff RH | title = TIM family of genes in immunity and tolerance | journal = Advances in Immunology | volume = 91 | issue = 1 | pages = 227–249 | date = April 2006 | pmid = 16938542 | pmc = | doi = 10.1016/S0065-2776(06)91006-2 | isbn = 9780120224913 }} 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.{{cite journal | vauthors = Rezaei M, Tan J, Zeng C, Li Y, Ganjalikhani-Hakemi M | title = TIM-3 in Leukemia; Immune Response and Beyond | journal = Frontiers in Oncology | volume = 11 | issue = | pages = 753677 | date = 2021 | pmid = 34660319 | pmc = 8514831 | doi = 10.3389/fonc.2021.753677 | doi-access = free }}

HAVCR2 /TIM-3 is member of TIM immunoregulatory proteins family which is encoded by gene on mouse chromosome 11B1.1 and on human chromosome 5q33.2. This chromosomal region has been repeatedly linked with asthma, allergy and autoimmunity. The TIM gene family include another eight members (TIM-1–8) on mouse chromosome and three members (TIM-1, TIM-3 and TIM-4) on human chromosome.{{cite journal | vauthors = Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK, Umetsu DT | title = The costimulatory role of TIM molecules | journal = Immunological Reviews | volume = 229 | issue = 1 | pages = 259–270 | date = May 2009 | pmid = 19426227 | pmc = 3217781 | doi = 10.1111/j.1600-065x.2009.00772.x }}{{cite journal | vauthors = Wolf Y, Anderson AC, Kuchroo VK | title = TIM3 comes of age as an inhibitory receptor | journal = Nature Reviews. Immunology | volume = 20 | issue = 3 | pages = 173–185 | date = March 2020 | pmid = 31676858 | pmc = 7327798 | doi = 10.1038/s41577-019-0224-6 }}{{cite journal | vauthors = Kuchroo VK, Dardalhon V, Xiao S, Anderson AC | title = New roles for TIM family members in immune regulation | journal = Nature Reviews. Immunology | volume = 8 | issue = 8 | pages = 577–580 | date = August 2008 | pmid = 18617884 | doi = 10.1038/nri2366 | s2cid = 31248 }}

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), a glycosylated mucin domain of variable length located closer to the membrane {{cite journal | vauthors = Cao E, Zang X, Ramagopal UA, Mukhopadhaya A, Fedorov A, Fedorov E, Zencheck WD, Lary JW, Cole JL, Deng H, Xiao H, Dilorenzo TP, Allison JP, Nathenson SG, Almo SC | title = T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface | journal = Immunity | volume = 26 | issue = 3 | pages = 311–321 | date = March 2007 | pmid = 17363302 | doi = 10.1016/j.immuni.2007.01.016 | doi-access = free }} 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. Cysteine bridges create a CC´ loop and an FG loop in the domain which make unique cleft characteristics for TIM-3 proteins. The cleft is stabilized by disulfide and hydrogen bonds and is a binding site for ligands such as CEACAM-1 and phosphatidylserine.{{cite journal | vauthors = Ocaña-Guzman R, Torre-Bouscoulet L, Sada-Ovalle I | title = TIM-3 Regulates Distinct Functions in Macrophages | journal = Frontiers in Immunology | volume = 7 | pages = 229 | date = 2016-06-13 | pmid = 27379093 | pmc = 4904032 | doi = 10.3389/fimmu.2016.00229 | doi-access = free }} The extracellular portion of the IgV domain may also be glycosylated and this glycan-binding sites is recognizes by carbohydrate domain of another ligands galectin-9 (Gal-9). The mucin domain is variable in a member of the TIM family, in TIM3 it is the smallest domain and has regions rich in serine, proline and threonine. This region also contains target sites for O- and N-linked glycosylation. The transmembrane domain anchors the HAVCR2 protein in the cytoplasmic membrane of the cell.{{cite journal | vauthors = Gorman JV, Colgan JD | title = Regulation of T cell responses by the receptor molecule Tim-3 | journal = Immunologic Research | volume = 59 | issue = 1–3 | pages = 56–65 | date = August 2014 | pmid = 24825777 | pmc = 4125508 | doi = 10.1007/s12026-014-8524-1 }} The 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,{{cite journal | vauthors = Lee J, Su EW, Zhu C, Hainline S, Phuah J, Moroco JA, Smithgall TE, Kuchroo VK, Kane LP | title = Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways | journal = Molecular and Cellular Biology | volume = 31 | issue = 19 | pages = 3963–3974 | date = October 2011 | pmid = 21807895 | pmc = 3187355 | doi = 10.1128/MCB.05297-11 }}{{cite journal | vauthors = van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW | title = A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9 | journal = Biochemical and Biophysical Research Communications | volume = 351 | issue = 2 | pages = 571–576 | date = December 2006 | pmid = 17069754 | doi = 10.1016/j.bbrc.2006.10.079 }} mediates intercellular signaling pathways and negatively regulates its function.{{cite journal | vauthors = Tomkowicz B, Walsh E, Cotty A, Verona R, Sabins N, Kaplan F, Santulli-Marotto S, Chin CN, Mooney J, Lingham RB, Naso M, McCabe T | title = TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression through the NFAT Signaling Pathway | journal = PLOS ONE | volume = 10 | issue = 10 | pages = e0140694 | date = 2015 | pmid = 26492563 | pmc = 4619610 | doi = 10.1371/journal.pone.0140694 | doi-access = free | bibcode = 2015PLoSO..1040694T }}

HAVCR2/TIM-3 is a transmembrane protein of T lymphocytes (CD4⁺ and CD8⁺ T cells), other lymphocytes (like NK cells), myeloid cells (monocytes, macrophages, DC, mast cells), or various cells in different tumor types. The receptor is an immune checkpoint and together with other inhibitory receptors including programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 protein (LAG3) mediate the CD8+ T-cell exhaustion in terms of proliferation and secretion of cytokines such as TNF-alpha, IFN-gamma and IL-2.{{cite journal | vauthors = Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ | title = Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection | journal = Nature Immunology | volume = 10 | issue = 1 | pages = 29–37 | date = January 2009 | pmid = 19043418 | pmc = 2605166 | doi = 10.1038/ni.1679 }}{{cite journal | vauthors = Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, Freeman GJ, Kuchroo VK, Ahmed R | title = Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 33 | pages = 14733–14738 | date = August 2010 | pmid = 20679213 | pmc = 2930455 | doi = 10.1073/pnas.1009731107 | bibcode = 2010PNAS..10714733J | doi-access = free }} Combined blockade of HAVCR2 and PD-1 led to improved CD8+ T-cell response during the lymphocytic choriomeningitis virus infection. HAVCR2 and PD-1 may be responsible for NK cell exhaustion as well.{{cite journal | vauthors = Zheng Y, Li Y, Lian J, Yang H, Li F, Zhao S, Qi Y, Zhang Y, Huang L | title = TNF-α-induced Tim-3 expression marks the dysfunction of infiltrating natural killer cells in human esophageal cancer | journal = Journal of Translational Medicine | volume = 17 | issue = 1 | pages = 165 | date = May 2019 | pmid = 31109341 | pmc = 6528366 | doi = 10.1186/s12967-019-1917-0 | doi-access = free }} Similarly, HAVCR2/TIM-3 and VSIR/VISTA may co-exist on macrophages infiltrating different human and mouse tumours where they can co-regulate immunotherapy resistance. HAVCR2 has also been shown as a CD4+ Th1-specific cell surface protein that regulates macrophage activation, regulates the production of cytokines and enhances the severity of experimental autoimmune encephalomyelitis in mice. Is also known the free form of HAVCR2 outside the cell membrane (soluble form), lacking mucin and the transmembrane domain. However, the function of the soluble protein is unknown.

HAVCR2 is primarily activated by soluble galectin-9.{{cite journal | vauthors = Wada J, Kanwar YS | title = Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin | journal = The Journal of Biological Chemistry | volume = 272 | issue = 9 | pages = 6078–6086 | date = February 1997 | pmid = 9038233 | doi = 10.1074/jbc.272.9.6078 | doi-access = free }} The engagement leads to stimulation of an influx of calcium to intracellular space and induction of programmed cell death, apoptosis, cell necrosis or T cell anergy.{{cite journal | vauthors = Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK | title = The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity | journal = Nature Immunology | volume = 6 | issue = 12 | pages = 1245–1252 | date = December 2005 | pmid = 16286920 | doi = 10.1038/ni1271 | s2cid = 24886582 }} 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. In addition to galectin-9, several ligands have been identified, such as phosphatidylserine (PtdSer),{{cite journal | vauthors = DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM | title = T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells | journal = Journal of Immunology | volume = 184 | issue = 4 | pages = 1918–1930 | date = February 2010 | pmid = 20083673 | pmc = 3128800 | doi = 10.4049/jimmunol.0903059 }} High Mobility Group Protein 1 (HMGB1){{cite journal | vauthors = Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, Hirashima M, Uede T, Takaoka A, Yagita H, Jinushi M | title = Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1 | journal = Nature Immunology | volume = 13 | issue = 9 | pages = 832–842 | date = September 2012 | pmid = 22842346 | pmc = 3622453 | doi = 10.1038/ni.2376 }} and Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1).

PtdSer is exposed on the surface of apoptotic cells and binds through the FG loop in the IgV domain. The binding of PtdSer with TIM-3 receptor has been shown to cause an uptake of apoptotic cells and is responsible for the cross-presentation of dying cell-associated antigens by dendritic cells.{{cite journal | vauthors = Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K | title = Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation | journal = Blood | volume = 113 | issue = 16 | pages = 3821–3830 | date = April 2009 | pmid = 19224762 | doi = 10.1182/blood-2008-10-185884 | s2cid = 2539786 }} PtdSer binds to the opposite side of the IgV domain of TIM-3 than Gal-9, and although this interaction of PtdSer to TIM-3 has five times less affinity than other members of the TIM family, Tim-3 can also bind some other ligand to phagocytose apoptotic cells.

HMGB1 is alarmin and interacts with DNA released from dying cells or pathogen nucleid acid, facilitating absorption by cell and increasing nucleic acid sensing by endosomal Toll-like receptors (TLRs).  HMGB1 binds to HAVCRS2/TIM3 on dendritic cells but its binding site has not been determined. TIM-3 receptor prevents the entry of the nucleic acids into the cell and suppresses activation of TLR signaling in dendritic cells. So the binding of HMGB1suppresses activation of innate immune response.

The last known TIM3 receptor ligand is CEACAM1 glycoprotein. It is co-expressed with TIM3 T cells but also monocytes, macrophages, dendritic cells. It binds to the CC´ and FG loops of the TIM3 protein. CEACAM1 can also bind to TIM3 intracellularly (cis presentation) and is likely to be important for TIM-3 maturation on cell surface. The CEACAM1 binding contributes to the development of T cell tolerance, triggers the release of BAT3 from TIM-3 leading to inhibition of TCR signaling, and also inhibits the immune response of myeloid cells.

File:Lung cancer HAVCR2.jpg

HAVCR2 expression is up regulated in tumor-infiltrating lymphocytes in lung, gastric,{{cite journal | vauthors = Lu X, Yang L, Yao D, Wu X, Li J, Liu X, Deng L, Huang C, Wang Y, Li D, Liu J | title = Tumor antigen-specific CD8⁺ T cells are negatively regulated by PD-1 and Tim-3 in human gastric cancer | journal = Cellular Immunology | volume = 313 | pages = 43–51 | date = March 2017 | pmid = 28110884 | doi = 10.1016/j.cellimm.2017.01.001 }} head and neck cancer,{{cite journal | vauthors = Shayan G, Srivastava R, Li J, Schmitt N, Kane LP, Ferris RL | title = Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer | journal = Oncoimmunology | volume = 6 | issue = 1 | pages = e1261779 | date = 2017 | pmid = 28197389 | pmc = 5283618 | doi = 10.1080/2162402X.2016.1261779 }} schwannoma,{{cite journal | vauthors = Li Z, Liu X, Guo R, Wang P | title = TIM-3 plays a more important role than PD-1 in the functional impairments of cytotoxic T cells of malignant Schwannomas | journal = Tumour Biology | volume = 39 | issue = 5 | pages = 1010428317698352 | date = May 2017 | pmid = 28475007 | doi = 10.1177/1010428317698352 | doi-access = free }} melanoma{{cite journal | vauthors = Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM | title = Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients | journal = The Journal of Experimental Medicine | volume = 207 | issue = 10 | pages = 2175–2186 | date = September 2010 | pmid = 20819923 | pmc = 2947081 | doi = 10.1084/jem.20100637 }} and follicular B-cell non-Hodgkin lymphoma.{{cite journal | vauthors = Yang ZZ, Grote DM, Ziesmer SC, Niki T, Hirashima M, Novak AJ, Witzig TE, Ansell SM | title = IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma | journal = The Journal of Clinical Investigation | volume = 122 | issue = 4 | pages = 1271–1282 | date = April 2012 | pmid = 22426209 | pmc = 3314462 | doi = 10.1172/JCI59806 }} It is also up-regulated in tumour-associated macrophages in various malignancies, including melanoma, especially in immunotherapy-resistant context.

The HAVCR2 pathway may interact with the PD-1 pathway in the dysfunctional CD8⁺ T cells and Tregs in cancer.{{cite journal | vauthors = Anderson AC | title = Tim-3: an emerging target in the cancer immunotherapy landscape | journal = Cancer Immunology Research | volume = 2 | issue = 5 | pages = 393–398 | date = May 2014 | pmid = 24795351 | doi = 10.1158/2326-6066.CIR-14-0039 | s2cid = 20347477 | doi-access = }} HAVCR2 is mainly expressed on activated CD8⁺ T cells and suppresses macrophage activation following PD-1 inhibition.{{cite journal | vauthors = Dempke WC, Fenchel K, Uciechowski P, Dale SP | title = Second- and third-generation drugs for immuno-oncology treatment-The more the better? | journal = European Journal of Cancer | volume = 74 | pages = 55–72 | date = March 2017 | pmid = 28335888 | doi = 10.1016/j.ejca.2017.01.001 }} Upregulation was observed in tumors progressing after anti-PD-1 therapy.{{cite journal | vauthors = Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, Jones RE, Kulkarni MM, Kuraguchi M, Palakurthi S, Fecci PE, Johnson BE, Janne PA, Engelman JA, Gangadharan SP, Costa DB, Freeman GJ, Bueno R, Hodi FS, Dranoff G, Wong KK, Hammerman PS | title = Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints | journal = Nature Communications | volume = 7 | pages = 10501 | date = February 2016 | pmid = 26883990 | pmc = 4757784 | doi = 10.1038/ncomms10501 | bibcode = 2016NatCo...710501K }} This seems to be a form of adaptive resistance to immunotherapy. Multiple phase 1/2 clinical trials with anti-HAVCR2 monoclonal antibodies (LY3321367,{{ClinicalTrialsGov|NCT03099109|A Study of LY3321367 Alone or With LY3300054 in Participants With Advanced Relapsed/Refractory Solid Tumors}} Eli Lilly and Company; MBG453,{{ClinicalTrialsGov|NCT02608268|Safety and Efficacy of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies}} Novartis Pharmaceuticals; TSR-022,{{ClinicalTrialsGov|NCT02817633|Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors}} Tesaro, Inc.) in combination with anti-PD-1 or anti-PD-L1 therapies are ongoing.

HAVCR2 is also an exhaustion marker for NK cells. Blockade of this receptor can improve the NK cells antitumor activity in esophageal cancer, melanoma and lung adenocarcinoma.

The role of HAVCR2 in the T-cell dysfunction has been investigated in chronic viral infections. Together with PD-1, HAVCR2 negatively regulate CD8+ T-cells and thus, in vivo blockade of HAVCR2 and PD-1 led to the restoring of antiviral immunity.{{cite journal | vauthors = Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, Freeman GJ, Kuchroo VK, Ahmed R | title = Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 33 | pages = 14733–14738 | date = August 2010 | pmid = 20679213 | pmc = 2930455 | doi = 10.1073/pnas.1009731107 | doi-access = free | bibcode = 2010PNAS..10714733J }}

A recent genome-wide association study (GWAS) has found that genetic variations in HAVCR2 are associated with late-onset sporadic Alzheimer's disease (LOAD). HARVC2 is capable of interacting with amyloid-β precursor protein.{{cite journal | vauthors = Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, Rongve A, Børte S, Winsvold BS, Drange OK, Martinsen AE, Skogholt AH, Willer C, Bråthen G, Bosnes I, Nielsen JB, Fritsche LG, Thomas LF, Pedersen LM, Gabrielsen ME, Johnsen MB, Meisingset TW, Zhou W, Proitsi P, Hodges A, Dobson R, Velayudhan L, Heilbron K, Auton A, Sealock JM, Davis LK, Pedersen NL, Reynolds CA, Karlsson IK, Magnusson S, Stefansson H, Thordardottir S, Jonsson PV, Snaedal J, Zettergren A, Skoog I, Kern S, Waern M, Zetterberg H, Blennow K, Stordal E, Hveem K, Zwart JA, Athanasiu L, Selnes P, Saltvedt I, Sando SB, Ulstein I, Djurovic S, Fladby T, Aarsland D, Selbæk G, Ripke S, Stefansson K, Andreassen OA, Posthuma D | title = A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease | journal = Nature Genetics | volume = 53 | issue = 9 | pages = 1276–1282 | date = September 2021 | pmid = 34493870 | doi = 10.1038/s41588-021-00921-z| pmc = 10243600 | s2cid = 237442349 | issn=1061-4036 | url = https://research.vu.nl/en/publications/61f01aa9-6dc7-4213-be2a-d3fe622db488 | hdl = 1871.1/61f01aa9-6dc7-4213-be2a-d3fe622db488 | hdl-access = free }}

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