T-cell immunoglobulin mucin-3 (TIM-3), an immune checkpoint receptor, can suppress effector T-cell activity and is associated with T-cell and natural killer (NK)-cell exhaustion. Inhibition may boost innate and adaptive immune response.
T-cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint receptor that is expressed on a wide variety of immune cells, including cytotoxic T cells, regulatory T cells (Tregs), natural killer (NK) cells, and some antigen-presenting cells (APCs) such as dendritic cells (DCs).1,2
TIM-3 interacts with numerous ligands such as phosphatidylserine (PS), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), galectin-9, and high mobility group box 1 (HMGB1).1,3
On apoptotic cells, PS can impair T-cell function.4
PS or HMGB1 interactions with TIM-3 on tumor-infiltrating DCs may lead to impaired ability of DCs to activate T cells and promote inflammation.4-6
On cytotoxic T cells, TIM-3 binding to galectin-9 on immunosuppressive MDSCs can enhance MDSC expansion and suppressor activity.1,7
T-cell expression of TIM-3 and its co-expression with CEACAM1 correlate with T-cell exhaustion.1,8,9
TIM-3 suppresses both innate and adaptive immune cells.1,6
TIM-3 can indirectly suppress effector T-cell activity by acting on myeloid-derived suppressor cells (MDSCs), Tregs, and DCs.1,7,10
TIM-3 expression on Tregs can reduce T-cell function and proliferation.10
Increased TIM-3 expression on NK cells has also been linked to NK-cell exhaustion.1,11
Additionally, NK cell–expressed TIM-3 can interact with PS or galectin-9 to promote NK cell dysfunction.1,11,12
Preclinical data suggest that TIM-3 blockade can rescue NK-cell activity, promote tumor antigen processing, and reinvigorate exhausted T cells to restore their proliferation and function.1,8,11
TIM-3 is often co-expressed with other immune checkpoint receptors, and preclinical studies indicate that co-blockade of TIM-3 with another immune checkpoint receptor may further reinvigorate exhausted T cells.8,14,15
Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989-1004.
Han G, Chen G, Shen B, Li Y. Tim-3: an activation marker and activation limiter of innate immune cells. Front Immunol. 2013;4:449. doi:10.3389/fimmu.2013.00449.
Nakayama M, Akiba H, Takeda K, et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood. 2009;113(16):3821-3830.
Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev. 2010;235(1):172-189.
Maurya N, Gujar R, Gupta M, Yadav V, Verma S, Sen P. Immunoregulation of dendritic cells by the receptor T cell Ig and mucin protein-3 via Bruton's tyrosine kinase and c-Src. J Immunol. 2014;193(7):3417-3425.
Chiba S, Baghdadi M, Akiba H, et al. Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol. 2012;13(9):832-842.
Dardalhon V, Anderson AC, Karman J, et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J Immunol. 2010;185(3):1383-1392.
Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175-2186.
Zhang Y, Cai P, Li L, et al. Co-expression of TIM-3 and CEACAM1 promotes T cell exhaustion in colorectal cancer patients. Int Immunopharmacol. 2017;43:210-218.
Gautron A-S, Dominguez-Villar M, de Marcken M, Hafler DA. Enhanced suppressor function of TIM-3+FoxP3+ regulatory T cells. Eur J Immunol. 2014;44(9):2703-2711.
da Silva IP, Gallois A, Jimenez-Baranda S, et al. Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res. 2014;2(5):410-422.
Weber JK, Zhou R. Phosphatidylserine-induced conformational modulation of immune cell exhaustion-associated receptor TIM3. Sci Rep. 2017;7:13579. doi:10.1038/s41598-017-14064-x.
Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2014;2(5):393-398.
Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For Immunopathol Dis Therap. 2015;6(1-2):7-17.
Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187-2194.
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