TIM3 (CD366) | Other immune checkpoint proteins | IUPHAR/BPS Guide to PHARMACOLOGY

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TIM3 (CD366)

target has curated data in GtoImmuPdb

Target id: 2940

Nomenclature: TIM3 (CD366)

Family: Other immune checkpoint proteins, CD molecules

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 301 5q33.3 HAVCR2 hepatitis A virus cellular receptor 2 5
Mouse 1 281 11 B1.1 Havcr2 hepatitis A virus cellular receptor 2
Rat 1 282 10q21 Havcr2 hepatitis A virus cellular receptor 2
Previous and Unofficial Names
T-cell immunoglobulin mucin family member 3 | TIM-3 | TIMD-3
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
galectin 9 {Sp: Human}
Immunopharmacology Comments
TIM3 is an immunoglobulin type protein expressed exclusively on the surface of differentiated Th1 cells [5]. It is a co-inhibitory receptor immune checkpoint protein that regulates macrophage activation, and inhibits Th1-mediated auto- and alloimmune responses, and promotes immunological tolerance. TIM3 is an immuno-oncology drug target [1,6], and may provide an additional strategy for cancers that develop adaptive resistance to current PD-1/PD-L1 axis immune checkpoint inhibitor therapies [3]. LY3321367 and MBG453 are anti-TIM3 monoclonals in early stage clinical trial: LY3321367 in Phase 1 trial NCT03099109 with LY3300054 (a novel anti-PD-L1 checkpoint inhibitor), and MBG453 ± spartalizumab (PDR001, anti-PD-1) vs. both advanced solid tumours (NCT02608268, Phase 1/2) and hematological malignancies (NCT03066648, Phase 1). Symphogen have the anti-TIM3 mAb Sym023 in their immuno-oncology pipeline (see Phase 1 trial NCT03489343). Tesaro's anti-TIM3 mAb TSR-022 is also in Phase 1 development (NCT02817633).
Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   T-helper 1 cell (CL:0000545)
Comment:  TIM3 is a selective marker of differentiated Th1 cells. Upregulation of TIM3 expression is reported as a biomarker associated with adaptive resistance to PD-1 blockade.
References:  3
Immuno Cell Type:  Natural killer cells
Comment:  TIM3 is expressed by mature NK cells, including human decidual NK cells. Its expression is upregulated on NK cells from patients with melanoma and lung adenocarcinoma. Elevated expression impairs NK cell effector functions.
References:  2,4,7
Immuno Cell Type:  Innate lymphoid cells
Cell Ontology Term:   group 3 innate lymphoid cell (CL:0001071)
Comment:  TIM3 expression has been reported on human ILC3s.
References:  4
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 10 GO processes
GO:0030886 negative regulation of myeloid dendritic cell activation IMP
GO:2001189 negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell IDA
click arrow to show/hide IEA associations
GO:0002281 macrophage activation involved in immune response IEA
GO:0002859 negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target IEA
GO:0006954 inflammatory response IEA
GO:0034138 toll-like receptor 3 signaling pathway IEA
GO:0034154 toll-like receptor 7 signaling pathway IEA
GO:0034162 toll-like receptor 9 signaling pathway IEA
GO:0043032 positive regulation of macrophage activation IEA
GO:0045087 innate immune response IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 6 GO processes
GO:2001189 negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell IDA
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
GO:0002652 regulation of tolerance induction dependent upon immune response IEA
GO:0002826 negative regulation of T-helper 1 type immune response IEA
GO:0042102 positive regulation of T cell proliferation IEA
GO:0042130 negative regulation of T cell proliferation IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 13 GO processes
GO:0030886 negative regulation of myeloid dendritic cell activation IMP
GO:2001189 negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell IDA
click arrow to show/hide IEA associations
GO:0002652 regulation of tolerance induction dependent upon immune response IEA
GO:0002826 negative regulation of T-helper 1 type immune response IEA
GO:0002859 negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target IEA
GO:0032815 negative regulation of natural killer cell activation IEA
GO:0034138 toll-like receptor 3 signaling pathway IEA
GO:0034154 toll-like receptor 7 signaling pathway IEA
GO:0034162 toll-like receptor 9 signaling pathway IEA
GO:0042102 positive regulation of T cell proliferation IEA
GO:0042130 negative regulation of T cell proliferation IEA
GO:0043032 positive regulation of macrophage activation IEA
GO:2000521 negative regulation of immunological synapse formation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 2 GO processes
GO:0002519 natural killer cell tolerance induction IMP
click arrow to show/hide IEA associations
GO:0002652 regulation of tolerance induction dependent upon immune response IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 12 GO processes
GO:0032687 negative regulation of interferon-alpha production IDA
GO:0032689 negative regulation of interferon-gamma production IDA
GO:0032703 negative regulation of interleukin-2 production IDA
GO:0032712 negative regulation of interleukin-3 production IDA
GO:0032720 negative regulation of tumor necrosis factor production IMP
GO:0032753 positive regulation of interleukin-4 production IMP
GO:0071656 negative regulation of granulocyte colony-stimulating factor production IDA
GO:1904469 positive regulation of tumor necrosis factor secretion IMP
click arrow to show/hide IEA associations
GO:0032715 negative regulation of interleukin-6 production IEA
GO:0032722 positive regulation of chemokine production IEA
GO:0032729 positive regulation of interferon-gamma production IEA
GO:0032732 positive regulation of interleukin-1 production IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 4 GO processes
GO:2001189 negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell IDA
click arrow to show/hide IEA associations
GO:0032722 positive regulation of chemokine production IEA
GO:0042102 positive regulation of T cell proliferation IEA
GO:0042130 negative regulation of T cell proliferation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 11 GO processes
GO:0030886 negative regulation of myeloid dendritic cell activation IMP
GO:2001189 negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell IDA
click arrow to show/hide IEA associations
GO:0002281 macrophage activation involved in immune response IEA
GO:0032815 negative regulation of natural killer cell activation IEA
GO:0034138 toll-like receptor 3 signaling pathway IEA
GO:0034154 toll-like receptor 7 signaling pathway IEA
GO:0034162 toll-like receptor 9 signaling pathway IEA
GO:0042102 positive regulation of T cell proliferation IEA
GO:0042130 negative regulation of T cell proliferation IEA
GO:0043032 positive regulation of macrophage activation IEA
GO:2000521 negative regulation of immunological synapse formation IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 3 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
GO:0002652 regulation of tolerance induction dependent upon immune response IEA
GO:0002826 negative regulation of T-helper 1 type immune response IEA
General Comments
This protein contains an immunoglobulin (Ig)-like domain that resembles the antibody variable domain, that has been coined the 'V-set domain'. The genes for all human V-set domain containing proteins are listed in HGNC gene group 590. The C-type lectin galectin-9 is a TIM3 ligand [1].

References

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1. Anderson AC. (2014) Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res, 2 (5): 393-8. [PMID:24795351]

2. da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, Osman I, Bhardwaj N. (2014) Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res, 2 (5): 410-22. [PMID:24795354]

3. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H et al.. (2016) Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun, 7: 10501. [PMID:26883990]

4. Mariotti FR, Quatrini L, Munari E, Vacca P, Moretta L. (2019) Innate Lymphoid Cells: Expression of PD-1 and Other Checkpoints in Normal and Pathological Conditions. Front Immunol, 10: 910. [PMID:31105707]

5. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA et al.. (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature, 415 (6871): 536-41. [PMID:11823861]

6. Romero D. (2016) Immunotherapy: PD-1 says goodbye, TIM-3 says hello. Nat Rev Clin Oncol, 13 (4): 202-3. [PMID:26977783]

7. Xu L, Huang Y, Tan L, Yu W, Chen D, Lu C, He J, Wu G, Liu X, Zhang Y. (2015) Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int. Immunopharmacol., 29 (2): 635-641. [PMID:26428847]

How to cite this page

Other immune checkpoint proteins: TIM3 (CD366). Last modified on 07/08/2019. Accessed on 23/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2940.