Tim‐3 and its role in regulating anti‐tumor immunity

Das, Madhumita; Zhu, Chen; Kuchroo, Vijay K.

doi:10.1111/imr.12520

Cited by 856Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Tim‐3 and its role in regulating anti‐tumor immunity

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Das, Madhumita, Zhu, Chen, Kuchroo, Vijay K.·2017·Immunological Reviews

DOI 10.1111/imr.12520PMC PMC5512889

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Abstract

Immunotherapy is being increasingly recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA-4 and PD-1 have achieved durable responses in melanoma, renal cancer, Hodgkin's diseases and lung cancer. However, the success rate of these treatments has been low and a large number of cancers, including colorectal cancer remain largely refractory to CTLA-4 and PD-1 blockade. This has provided impetus to identify other co-inhibitory receptors that could be exploited to enhance response rates of current immunotherapeutic agents and achieve responses to the cancers that are refectory to immunotherapy. Tim-3 is a co-inhibitory receptor that is expressed on IFN-g-producing T cells, FoxP3+ Treg cells and innate immune cells (macrophages and dendritic cells) where it has been shown to suppress their responses upon interaction with their ligand(s). Tim-3 has gained prominence as a potential candidate for cancer immunotherapy, where it has been shown that in vivo blockade of Tim-3 with other check-point inhibitors enhances anti-tumor immunity and suppresses tumor growth in several preclinical tumor models. This review discusses the recent findings on Tim-3, the role it plays in regulating immune responses in different cell types and the rationale for targeting Tim-3 for effective cancer immunotherapy.

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TIM-3 is an important immunoreceptor involved in T-cell exhaustion, leading to inactivation of these cells.
“Furthermore, T-cell immunoglobulin and mucin domain-3 (TIM-3) have been identified as important immunoreceptors involved in T-cell exhaustion, leading to the inactivation of these cells [58].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [58]
ICOS and TIM3 expressions on specific T cell subsets are related to antitumor immunity.
“ICOS and TIM3 expressions on specific T cells subsets are also related to antitumor immunity.52,53”
From The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC (2019) · cites this paper as [52]
The binding state of TIM-3 with ligands activates the phosphorylation of Tyr256 and Tyr263 tyrosine residues by IL-2-inducible T cell kinase (ITK), followed by ligand binding, releasing BAT3 into the cytoplasm.
“The binding state of TIM‐3 with ligands activates the phosphorylation of Tyr256 and Tyr263 tyrosine residues by IL‐2‐inducible T cell kinase (ITK), followed by ligand binding, releasing BAT3 into the cytoplasm [310, 311].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [311]

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Self-citation
A highly conserved tyrosine of Tim‐3 is phosphorylated upon stimulation by its ligand galectin‐9
van de Weyer, P. S., Muehlfeit, M., Klose, C., Bonventre, J. V., Walz, G., & Kuehn, E. W. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.10.079 · Cited by 198 · see citing works
Tim3 binding to galectin-9 stimulates antimicrobial immunity
Jayaraman, P., Sada‐Ovalle, I., Beladi, S., Anderson, A. C., Dardalhon, V., Hotta, C., Kuchroo, V. K., & Behar, S. M. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20100687 · Cited by 198 · see citing works
Self-citation
Tim-3 Expression Defines Regulatory T Cells in Human Tumors
Yan, J., Zhang, Y., Zhang, J., Liang, J., Li, L., & Zheng, L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058006 · Cited by 183 · see citing works
Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy
Burton, B. R., Britton, G. J., Fang, H., Verhagen, J., Smithers, B., Sabatos-Peyton, C. A., Carney, L. J., Gough, J., Ströbel, S., & Wraith, D. C. (2014) · Nature Communications · doi:10.1038/ncomms5741 · Cited by 181 · see citing works
Decreased Galectin-9 and Increased Tim-3 Expression Are Related to Poor Prognosis in Gastric Cancer
Jiang, J., Jin, M., Kong, F., Cao, D., Ma, H., Jia, Z., Wang, Y., Suo, J., & Cao, X. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081799 · Cited by 172 · see citing works
TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells
Nakae, S., Iikura, M., Suto, H., Akiba, H., Umetsu, D. T., DeKruyff, R. H., Saito, H., & Galli, S. J. (2007) · Blood · doi:10.1182/blood-2006-11-058800 · Cited by 169 · see citing works
HMGB1: The Central Cytokine for All Lymphoid Cells
Li, G., Liang, X., & Lotze, M. T. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00068 · Cited by 167 · see citing works
Structures of T Cell Immunoglobulin Mucin Receptors 1 and 2 Reveal Mechanisms for Regulation of Immune Responses by the TIM Receptor Family
Santiago, C. A., Ballesteros, Á., Tami, C., Martínez‐Muñoz, L., Kaplan, G. G., & Casasnovas, J. M. (2007) · Immunity · doi:10.1016/j.immuni.2007.01.014 · Cited by 164 · see citing works
Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer
Kang, C.-W., Dutta, A., Chang, L.-Y., Mahalingam, J., Lin, Y., Chiang, J., Hsu, C.-Y., Huang, C., Su, W., Chu, Y., et al. (2015) · Scientific Reports · doi:10.1038/srep15659 · Cited by 162 · see citing works
PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy
Wang, S., Yh, L., Hl, P., Hong, X.-W., Zhang, D., Xu, Y.-Y., Yi, T., Wang, Y., Yuan, M.-M., Dj, L., et al. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.112 · Cited by 159 · see citing works
Blockade of T im‐3 signaling restores the virus‐specific CD 8+ T ‐cell response in patients with chronic hepatitis B
Wu, W., Shi, Y., Li, S., Zhang, Y., Liu, Y., Wu, Y., & Chen, Z. (2012) · European Journal of Immunology · doi:10.1002/eji.201141852 · Cited by 158 · see citing works
Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion
Huang, X., Bai, X., Cao, Y., Wu, J., Huang, M., Tang, D., Tao, S., Zhu, T., Liu, Y., Yang, Y., et al. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20090397 · Cited by 156 · see citing works
Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes
Zhang, Y., Cheng, J., Wang, J. M., Xiao, J., Wu, X. Y., Moorman, J. P., & Yao, Z. Q. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.1010591 · Cited by 149 · see citing works
Lack of TIM-3 Immunoregulation in Multiple Sclerosis
Yang, L., Anderson, D. E., Kuchroo, J. R., & Hafler, D. A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.7.4409 · Cited by 141 · see citing works
Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs
Gupta, S., Thornley, T. B., Gao, W., Larocca, R., Turka, L. A., Kuchroo, V. K., & Strom, T. B. (2012) · Journal of Clinical Investigation · doi:10.1172/jci45138 · Cited by 139 · see citing works
Self-citation
TIM-3 Is Expressed in Melanoma Cells and Is Upregulated in TGF-Beta Stimulated Mast Cells
Wiener, Z., Kőhalmi, B., Pócza, P., Jeager, J., Tölgyesi, G., Tóth, S., Görbe, É., Papp, Z., & Falus, A. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700616 · Cited by 139 · see citing works
A Disintegrin and Metalloprotease (ADAM) 10 and ADAM17 Are Major Sheddases of T Cell Immunoglobulin and Mucin Domain 3 (Tim-3)
Möller‐Hackbarth, K., Dewitz, C., Schweigert, O., Trad, A., Garbers, C., Rose‐John, S., & Scheller, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.488478 · Cited by 136 · see citing works
T Cell Ig and Mucin Domain–Containing Protein 3 Is Recruited to the Immune Synapse, Disrupts Stable Synapse Formation, and Associates with Receptor Phosphatases
Clayton, K. L., Haaland, M. S., Douglas-Vail, M. B., Mujib, S., Chew, G. M., Ndhlovu, L. C., & Ostrowski, M. A. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302663 · Cited by 134 · see citing works
Cutting Edge: T Cell Ig Mucin-3 Reduces Inflammatory Heart Disease by Increasing CTLA-4 during Innate Immunity
Frisancho‐Kiss, S., Nyland, J. F., Davis, S. E., Barrett, M. A., Gatewood, S. J. L., Njoku, D. B., Čiháková, D., Silbergeld, E. K., Rose, N. R., & Fairweather, D. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.11.6411 · Cited by 132 · see citing works
Tim-3-Galectin-9 pathway involves the suppression induced by CD4+CD25+ regulatory T cells
Wang, F., Wan, L., Zhang, C.-C., et al. (2008) · Immunobiology · doi:10.1016/j.imbio.2008.10.007 · Cited by 125 · see citing works
T‐bet, a Th1 transcription factor regulates the expression of Tim‐3
Anderson, A. C., Lord, G. M., Dardalhon, V., Lee, D. H., Sabatos-Peyton, C. A., Glimcher, L. H., & Kuchroo, V. K. (2010) · European Journal of Immunology · doi:10.1002/eji.200939842 · Cited by 121 · see citing works
Self-citation
The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas
Komohara, Y., Morita, T., Annan, D. A., Horlad, H., Ohnishi, K., Yamada, S., Nakayama, T., Kitada, S., Suzu, S., Kinoshita, I., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0156 · Cited by 116 · see citing works
Preferential Involvement of Tim-3 in the Regulation of Hepatic CD8+ T Cells in Murine Acute Graft-versus-Host Disease
Oikawa, T., Kamimura, Y., Akiba, H., Yagita∥, H., Okumura, K., Takahashi, H., Zeniya, M., Tajiri, H., & Azuma, M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.7.4281 · Cited by 114 · see citing works
Combinatorial Cancer Immunotherapies
Hellmann, M. D., Friedman, C. F., & Wolchok, J. D. (2016) · Advances in immunology · doi:10.1016/bs.ai.2015.12.005 · Cited by 108 · see citing works
Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors
Takamura, S., Tsuji-Kawahara, S., Yagita∥, H., Akiba, H., Sakamoto, M., Chikaishi, T., Kato, M., & Miyazawa, M. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903478 · Cited by 104 · see citing works
Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway
Mujib, S., Jones, R. B., Lo, C. C., Aidarus, N., Clayton, K., Sakhdari, A., Benko, E., Kovacs, C. M., & Ostrowski, M. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102609 · Cited by 101 · see citing works
Tim-3 Negatively Regulates IL-12 Expression by Monocytes in HCV Infection
Zhang, Y., Cheng, J., Wang, J. M., Xiao, J., Wu, X. Y., Jia, Z., Moorman, J. P., & Yao, Z. Q. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019664 · Cited by 100 · see citing works
Tim-3-Expressing CD4+ and CD8+ T Cells in Human Tuberculosis (TB) Exhibit Polarized Effector Memory Phenotypes and Stronger Anti-TB Effector Functions
Qiu, Y., Chen, J., Liao, H., Zhang, Y., Wang, H., Li, S., Luo, Y., Fang, D., Li, G., Zhou, B., et al. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002984 · Cited by 94 · see citing works
Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer
Guo, Z., Cheng, D., Xia, Z., Luan, M., Wu, L., Wang, G., & Zhang, S. (2013) · Journal of Translational Medicine · doi:10.1186/1479-5876-11-215 · Cited by 94 · see citing works
Increased Tim-3 expression on peripheral lymphocytes from patients with rheumatoid arthritis negatively correlates with disease activity.
Liu, Y., Shu, Q., Gao, L.-F., Hou, N., Zhao, D., Liu, X., Zhang, X., Xu, L.-Y., Yue, X.-T., Zhu, F., et al. (2010) · Clinical Immunology · doi:10.1016/j.clim.2010.07.012 · Cited by 92 · see citing works
Tim-3 Directly Enhances CD8 T Cell Responses to Acute Listeria monocytogenes Infection
Gorman, J. V., Starbeck-Miller, G. R., Pham, N., Traver, G. L., Rothman, P. B., Harty, J. T., & Colgan, J. D. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302290 · Cited by 90 · see citing works
A Novel Soluble Form of Tim-3 Associated with Severe Graft-versus-Host Disease
Hansen, J. A., Hanash, S., Tabellini, L., Baik, C., Lawler, R. L., Grogan, B. M., Storer, B. E., Chin, A. P., Johnson, M. M., Wong, C., et al. (2013) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2013.06.011 · Cited by 88 · see citing works
Galectin-9 and T Cell Immunoglobulin Mucin-3 Pathway Is a Therapeutic Target for Type 1 Diabetes
Kanzaki, M., Wada, J., Sugiyama, K., Nakatsuka, A., Teshigawara, S., Murakami, K., Inoue, K., Terami, T., Katayama, A., Eguchi, J., et al. (2011) · Endocrinology · doi:10.1210/en.2011-1579 · Cited by 86 · see citing works
Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer.
Zhou, E., Huang, Q. B., Wang, J., Fang, C., Yang, L., Zhu, M., Chen, J., Chen, L., & Dong, M. (2015) · PubMed Central · Cited by 85 · see citing works
The Clinical Significance of Abnormal Tim-3 Expression on NK Cells from Patients with Gastric Cancer
Wang, Z., Zhu, J., Gu, H., Yuan, Y., Zhang, B., Zhu, D., Zhou, J., Zhu, Y., & Chen, W. (2015) · Immunological Investigations · doi:10.3109/08820139.2015.1052145 · Cited by 79 · see citing works
Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection
Wu, W., Shi, Y., Li, J., Chen, F., Chen, Z. J., & Zheng, M. (2011) · Virology Journal · doi:10.1186/1743-422x-8-113 · Cited by 78 · see citing works
T‐cell immunoglobulin mucin‐3 expression in bladder urothelial carcinoma: Clinicopathologic correlations and association with survival
Yang, M., Yu, Q., Liu, J., et al. (2015) · Journal of Surgical Oncology · doi:10.1002/jso.24012 · Cited by 75 · see citing works
Prognostic implication of TIM-3 in clear cell renal cell carcinoma
Yuan, J., Jiang, B., Zhao, H., & Huang, Q. B. (2013) · Neoplasma · doi:10.4149/neo_2014_006 · Cited by 68 · see citing works
Dysfunction of PSA-specific CD8+ T cells in prostate cancer patients correlates with CD38 and Tim-3 expression
Japp, A. S., Kursunel, M. A., Meier, S., Mälzer, J. N., Li, X., Rahman, N. A., Jekabsons, W., Krause, H., Magheli, A., Klopf, C., et al. (2015) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-015-1752-y · Cited by 65 · see citing works
Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells
Veenstra, R. G., Taylor, P. A., Zhou, Q., et al. (2012) · Blood · doi:10.1182/blood-2011-10-387977 · Cited by 64 · see citing works
TIM-3 expression in human osteosarcoma: Correlation with the expression of epithelial-mesenchymal transition-specific biomarkers
Shang, Y., LI, Z., Li, H., Xia, H., & Lin, Z. (2013) · Oncology Letters · doi:10.3892/ol.2013.1410 · Cited by 64 · see citing works
Ovarian carcinoma-infiltrating regulatory T cells were more potent suppressors of CD8+ T cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression
Bu, M., Shen, Y., Seeger, W. L., et al. (2015) · Tumor Biology · doi:10.1007/s13277-015-4237-x · Cited by 63 · see citing works
Tim-3 promotes intestinal homeostasis in DSS colitis by inhibiting M1 polarization of macrophages
Jiang, X., Yu, J., Shi, Q., Xiao, Y., Wang, W., Chen, G., Zhao, Z. J., Wang, R., He, X., Hou, C., et al. (2015) · Clinical Immunology · doi:10.1016/j.clim.2015.07.008 · Cited by 62 · see citing works
Immunoregulation of Dendritic Cells by the Receptor T cell Ig and Mucin Protein-3 via Bruton’s Tyrosine Kinase and c-Src
Maurya, N., Gujar, R., Gupta, M., Yadav, V., Verma, S., & Sen, P. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400395 · Cited by 62 · see citing works
Prognostic Value of T Cell Immunoglobulin Mucin-3 in Prostate Cancer
Piao, Y.-R., Piao, L., Zhu, L., Jin, Z., & Dong, X.-Z. (2013) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2013.14.6.3897 · Cited by 60 · see citing works
Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells
Silva, I. G., Gibbs, B. F., Bardelli, M., Varani, L., & Sumbayev, V. V. (2015) · Oncotarget · doi:10.18632/oncotarget.5257 · Cited by 57 · see citing works
The immune receptor Tim-3 mediates activation of PI3 kinase/mTOR and HIF-1 pathways in human myeloid leukaemia cells
Prokhorov, A., Gibbs, B. F., Bardelli, M., Rüegg, L., Fasler‐Kan, E., Varani, L., & Sumbayev, V. V. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.11.017 · Cited by 53 · see citing works
Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-Cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice
Dolina, J. S., Braciale, T. J., & Hahn, Y. S. (2013) · Hepatology · doi:10.1002/hep.26938 · Cited by 49 · see citing works
Cis Association of Galectin-9 with Tim-3 Differentially Regulates IL-12/IL-23 Expressions in Monocytes via TLR Signaling
Cheng, J., Li, G. Y., Cheng, Y., Wang, J. M., Ying, R. S., Shi, L., Wu, X. Y., Niki, T., Hirashima, M., Li, C. F., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072488 · Cited by 47 · see citing works
Tim‐3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients
Sada‐Ovalle, I., Ocaña‐Guzmán, R., Pérez-Patrigeón, S., et al. (2015) · Journal of the International AIDS Society · doi:10.7448/ias.18.1.20078 · Cited by 44 · see citing works
T cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and susceptibility to pancreatic cancer
Tong, D., Zhou, Y., Chen, W., Deng, Y., Li, L., Jia, Z., & Qi, D. (2012) · Molecular Biology Reports · doi:10.1007/s11033-012-1862-y · Cited by 43 · see citing works
Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives TH17 Cell Development during Hepatitis C Virus Infection
Wang, J. M., Shi, L., Cheng, J., Xiao, J., Ying, R. S., Wu, X. Y., Wang, K. S., Li, G., Moorman, J. P., & Yao, Z. Q. (2013) · Journal of Virology · doi:10.1128/jvi.03376-12 · Cited by 42 · see citing works
A role for the TIM‐3/GAL‐9/BAT3 pathway in determining the clinical phenotype of multiple sclerosis
Saresella, M., Piancone, F., Marventano, I., Rosa, F. L., Tortorella, P., Caputo, D., Rovaris, M., & Clerici, M. (2014) · The FASEB Journal · doi:10.1096/fj.14-258194 · Cited by 39 · see citing works
Expression of TIM‐3 on CD4+ and CD8+ T cells in the peripheral blood and synovial fluid of rheumatoid arthritis
Li, S., Peng, D., He, Y., et al. (2014) · Apmis · doi:10.1111/apm.12228 · Cited by 38 · see citing works
Tim-3 alters the balance of IL-12/IL-23 and drives TH17 cells: Role in hepatitis B vaccine failure during hepatitis C infection
Wang, J. M., Cheng, J., Li, G. Y., Wu, X. Y., Thayer, P., Greer, P., Smith, A. M., High, K. P., Moorman, J. P., & Yao, Z. Q. (2013) · Vaccine · doi:10.1016/j.vaccine.2013.03.003 · Cited by 38 · see citing works
Interferon-β Suppresses Murine Th1 Cell Function in the Absence of Antigen-Presenting Cells
Boivin, N., Baillargeon, J., Doss, P. M. I. A., Roy, A.-P., & Rangachari, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124802 · Cited by 36 · see citing works
Genetic variations and haplotypes in TIM-3 gene and the risk of gastric cancer
Cao, B., Zhu, L., Zhu, S., et al. (2010) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-010-0910-5 · Cited by 36 · see citing works
T-cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and prognosis of non-small-cell lung cancer
Bai, J., Li, X., Tong, D., Shi, W., Song, H., & Li, Q. (2013) · Tumor Biology · doi:10.1007/s13277-012-0610-1 · Cited by 30 · see citing works
Down-regulation of interleukin-2 production by CD4+ T cells expressing TIM-3 through suppression of NFAT dephosphorylation and AP-1 transcription
Lee, M. J., Woo, M.-Y., Chwae, Y., Kwon, M., Kim, K. H., & Park, S. (2012) · Immunobiology · doi:10.1016/j.imbio.2012.01.012 · Cited by 27 · see citing works
Dysregulated upregulation of T-cell immunoglobulin and mucin domain-3 on mucosal T helper 1 cells in patients with Crohn's disease
Morimoto, K., Hosomi, S., Yamagami, H., et al. (2011) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365521.2011.568518 · Cited by 24 · see citing works

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Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy
Lei, X., Lei, Y., Li, J.-K., Du, W.-X., Li, R.-G., Yang, J., Li, J., Li, F., & Tan, H.-B. (2020) · Cancer Letters · doi:10.1016/j.canlet.2019.11.009 · Cited by 1,470 · see citing works
Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4
Qin, S., Xu, L., Yi, M., Yu, S., Wu, K., & Luo, S. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1091-2 · Cited by 1,145 · see citing works
Harnessing innate immunity in cancer therapy
Demaria, O., Cornen, S., Daëron, M., Morel, Y., Medzhitov, R., & Vivier, E. (2019) · Nature · doi:10.1038/s41586-019-1593-5 · Cited by 957 · see citing works
The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC
Jin, Y., Dong, H., Xia, L., Yang, Y., Zhu, Y., Shen, Y., Zheng, H., Yao, C., Wang, Y., & Lu, S. (2019) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2019.04.007 · Cited by 573 · see citing works
T Cell Exhaustion
Baessler, A., & Vignali, D. A. A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-110914 · Cited by 420 · see citing works
Tumor microenvironment signaling and therapeutics in cancer progression
Goenka, A., Khan, F., Verma, B., Sinha, P., Dmello, C. C., Jogalekar, M. P., Gangadaran, P., & Ahn, B. (2023) · Cancer Communications · doi:10.1002/cac2.12416 · Cited by 323 · see citing works
Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody
Harding, J. J., Moreno, V., Bang, Y.-J., Hong, M. H., Patnaik, A., Trigo, J., Szpurka, A. M., Yamamoto, N., Doi, T., Fu, S., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-4405 · Cited by 161 · see citing works
Tim-3 Hampers Tumor Surveillance of Liver-Resident and Conventional NK Cells by Disrupting PI3K Signaling
Tan, S., Xu, Y., Wang, Z., Wang, T., Du, X., Song, X., Guo, X., Peng, J., Zhang, J., Liang, Y., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-2332 · Cited by 147 · see citing works
Combination of Immunotherapy With Targeted Therapy: Theory and Practice in Metastatic Melanoma
Yu, C., Liu, X., Yang, J., Zhang, M., Jin, H., Ma, X., & Shi, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00990 · Cited by 126 · see citing works
Single-cell multiomics analysis reveals regulatory programs in clear cell renal cell carcinoma
Long, Z., Sun, C., Tang, M., Wang, Y., Ma, J., Yu, J., Wei, J., Ma, J., Wang, B., Xie, Q., et al. (2022) · Cell Discovery · doi:10.1038/s41421-022-00415-0 · Cited by 109 · see citing works
Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review
Li, Y., Zhang, C., Jiang, A., Lin, A., Liu, Z., Cheng, X., Wang, W., Cheng, Q., Zhang, J., Wei, T., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05104-y · Cited by 105 · see citing works
“During the development of the immuno-suppressive microenvironment surrounding tumors, various subpopulations of Tregs expressing diverse immunosuppressive molecules are crucial, each having distinct immune checkpoints [168, 169].”
Background
Immune checkpoint inhibitors associated cardiovascular immune-related adverse events
Jo, W., Won, T., Daoud, A., & Čiháková, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1340373 · Cited by 55 · see citing works
Immune checkpoint inhibitors for multiple myeloma immunotherapy
Liu, Z., Xu, X., Liu, H., Zhao, X., Yang, C., & Fu, R. (2023) · Experimental Hematology & Oncology · doi:10.1186/s40164-023-00456-5 · Cited by 40 · see citing works
The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors
Evmorfopoulos, K., Marsitopoulos, K., Karachalios, R., Karathanasis, A., Dimitropoulos, K., Tzortzis, V., Zachos, I., & Vlachostergios, P. J. (2024) · Cancers · doi:10.3390/cancers16020428 · Cited by 11 · see citing works
“Furthermore, T-cell immunoglobulin and mucin domain-3 (TIM-3) have been identified as important immunoreceptors involved in T-cell exhaustion, leading to the inactivation of these cells [58].”
Background

Inhibiting Immune Checkpoints for the Treatment of Bladder Cancer
Bidnur, S., Savdie, R., & Black, P. C. (2016) · Bladder Cancer · doi:10.3233/blc-150026 · Cited by 35 · see citing works
A progressive T cell exhaustion program mapped across tissues in patients with lung cancer on immune checkpoint blockade
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Distinct immunologic changes in vivo following combination versus individual PD-1 or CTLA-4 checkpoint blockade in human cancer
Dhodapkar, K. M., Verma, R., Sznol, M., et al. (2014) · Journal for ImmunoTherapy of Cancer · doi:10.1186/2051-1426-2-s3-o7
Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma
Grasso, C. S., Tsoi, J., Onyshchenko, M. I., Abril-Rodríguez, G., Ross‐Macdonald, P., Wind‐Rotolo, M., Champhekar, A. S., Medina, E., Torrejon, D. Y., Shin, D. S., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.11.015 · Cited by 53 · see citing works
Tumor organoid-originated biomarkers predict immune response to PD-1 blockade
Bozkus, C. C., & Bhardwaj, N. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.08.003 · Cited by 8 · see citing works

Authors: Das, M., Zhu, C., & Kuchroo, V. K.
Affiliations: Brigham and Women's Hospital (US)
Sanofi (United States) (US)
Broad Institute (US)
Corresponding author: Kuchroo, Vijay K.
ORCID: Das, Madhumita
Zhu, Chen
Kuchroo, Vijay K.
Venue: Immunological Reviews
Publisher: Wiley
Published: 2017-03
Volume: 276
Issue: 1
Pages: 97-111
ISSN: 0105-2896 (ISSN-L)
1600-065X
DOI: 10.1111/imr.12520
PMC: PMC5512889
OpenAlex: W2593059553
Cited by: 856
References: 122
Citations by year: 2026: 71 · 2025: 75 · 2024: 108 · 2023: 127 · 2022: 120 · 2021: 137 · 2020: 112 · 2019: 62 · 2018: 32 · 2017: 12
FWCI: 6.26
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3 d)
Locations: Immunological Reviews (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Allergy and Infectious Diseases (P01AI073748)
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 › Immunotherapy and Immune Responses
Keywords: TIM-3, co-inhibitory receptors, cancer immunotherapy, antitumor immunity, immune checkpoint blockade, Foxp3+ regulatory T cells, IFN-gamma-producing T cells, innate immune cells, colorectal cancer, tumor growth inhibition
MeSH terms: Hepatitis A Virus Cellular Receptor 2, Animals, Antigens, Neoplasm, Humans, Immunity, Immunotherapy, Interferon-gamma, Neoplasms, Tumor Escape, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Immunomodulation

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Tim‐3 and its role in regulating anti‐tumor immunity

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