TIM3 comes of age as an inhibitory receptor
Open accessAbstract
T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a member of the TIM family, was originally identified as a receptor expressed on interferon-γ-producing CD4+ and CD8+ T cells. Initial data indicated that TIM3 functioned as a 'co-inhibitory' or 'checkpoint' receptor, but due to the lack of a definable inhibitory signalling motif, it was also suggested that TIM3 might act as a co-stimulatory receptor. Recent studies have shown that TIM3 is part of a module that contains multiple co-inhibitory receptors (checkpoint receptors), which are co-expressed and co-regulated on dysfunctional or 'exhausted' T cells in chronic viral infections and cancer. Furthermore, co-blockade of TIM3 and programmed cell death 1 (PD1) can result in tumour regression in preclinical models and can improve anticancer T cell responses in patients with advanced cancers. Here, we highlight the developments in understanding TIM3 biology, including novel ligand identification and the discovery of loss-of-function mutations associated with human disease. In addition, we summarize emerging data from human clinical trials showing that TIM3 indeed acts as a 'checkpoint' receptor and that inhibition of TIM3 enhances the antitumour effect of PD1 blockade.
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HAVCR2 encodes the checkpoint molecule TIM3, a promising therapeutic approach in cancer, and was recently described in a GWAS as an AD risk gene.
“the latter of which encodes the checkpoint molecule TIM3, one of the most promising new therapeutic approaches in cancer 32 that was recently described in a GWAS as an AD risk gene 2 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [32]
Tyrosine kinase FYN and human leukocyte antigen B (HLA-B)-associated transcript 3 (BAT3) were suggested to inhibit the cytoplasmic tail of TIM-3 signaling.
“Nevertheless, tyrosine kinase FYN and human leukocyte antigen B (HLA‐B)‐associated transcript 3 (BAT3) were suggested to inhibit the cytoplasmic tail of TIM‐3 signaling [307, 308, 309].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [307]
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Lack of TIM-3 Immunoregulation in Multiple Sclerosis
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The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia
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Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs
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Self-citationTIM-3 Is Expressed in Melanoma Cells and Is Upregulated in TGF-Beta Stimulated Mast Cells
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T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response
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Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection
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T‐bet, a Th1 transcription factor regulates the expression of Tim‐3
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Self-citationGalectin-9 suppresses Th17 cell development in an IL-2-dependent but Tim-3-independent manner
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Galectin-9 regulates T helper cell function independently of Tim-3
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Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation
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Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma
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Immune Checkpoint Molecules in Reproductive Immunology
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TIM-3 Does Not Act as a Receptor for Galectin-9
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A Novel Soluble Form of Tim-3 Associated with Severe Graft-versus-Host Disease
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Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer
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Human Pregnancy Up-Regulates Tim-3 in Innate Immune Cells for Systemic Immunity
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Tim-3 promotes intestinal homeostasis in DSS colitis by inhibiting M1 polarization of macrophages
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TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells
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Impaired Expression of Tim-3 on Th17 and Th1 Cells in Psoriasis
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The association of TIM-3 gene polymorphism with atopic disease in Korean population
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Involvement of T cell Ig Mucin-3 (Tim-3) in the negative regulation of inflammatory bowel disease
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Identification of TIM-3 as a Leukemic Stem Cell Surface Molecule in Primary Acute Myeloid Leukemia
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Tim-3 as a diagnostic and prognostic biomarker of osteosarcoma
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Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2
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A role for the TIM‐3/GAL‐9/BAT3 pathway in determining the clinical phenotype of multiple sclerosis
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Discovery of TSR-022, a novel, potent anti-human TIM-3 therapeutic antibody
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Microglia activity modulated by T cell Ig and mucin domain protein 3 (Tim-3)
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Genetic Alterations and Expression Pattern of CEACAM1 in Colorectal Adenomas and Cancers
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Human disease mutations highlight the inhibitory function of TIM-3
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2 of the 159 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- [153]Weiss GJ A phase 1 study of TSR-022, an anti-TIM-3 monoclonal antibody, in patients (pts) with advanced solid tumors. J. Immunother. Cancer 5, 86 (2017).
- [154]Davar D A phase 1 study of TSR-022, an anti-TIM-3 monoclonal antibody, in combination with TSR-042 (anti-PD-1) in patients with colorectal cancer and post-PD-1 NSCLC and melanoma. J. Immunother. Cancer 6, 115 (2018).30400822
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Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion
Yan, R., Zhang, P., Shen, S., Zeng, Y., Wang, T., Chen, Z., Ma, W., Feng, J., Suo, C., Zhang, T., et al. (2024) · Nature Immunology · doi:10.1038/s41590-023-01719-3 · Cited by 63 · see citing works
- Authors
- Wolf, Y., Anderson, A. C., & Kuchroo, V. K.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Kuchroo, Vijay K.
- Venue
- Nature Reviews Immunology
- Published
- 2019-11-01
- Volume
- 20
- Issue
- 3
- Pages
- 173-185
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- PMC
- PMC7327798
- OpenAlex
- W2985205513
- Cited by
- 959
- References
- 159
- Citations by year
- 2026: 98 · 2025: 140 · 2024: 191 · 2023: 160 · 2022: 183 · 2021: 142 · 2020: 44
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA187975)
- National Institute of Allergy and Infectious Diseases (P01AI073748, P01AI056299, P01AI039671)
- National Institute of Neurological Disorders and Stroke (R01NS045937)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Keywords
- TIM-3, inhibitory receptors, co-inhibitory receptors, immune checkpoint, T cell exhaustion, loss-of-function mutations, antitumor immunity, chronic viral infection, cancer immunotherapy
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, Clinical Trials as Topic, Humans, Signal Transduction, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Programmed Cell Death 1 Receptor
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