Abstract
Background: T-cell immunoglobulin (Ig)-domain and mucin-domain (TIM) proteins represent a family of receptors expressed on T-cells that play essential cellular immunity roles. The TIM proteins span across the membrane belonging to type I transmembrane proteins. The N terminus contains an Ig-like V-type domain and a Ser/Thr-rich mucin stalk as a co-inhibitory receptor. The C-terminal tail oriented toward the cytosol predominantly mediates intracellular signaling.
Methods: This review discusses the structural features and functions of TIM-3, specifically on its role in mediating immune responses in different cell types and the rationale for TIM-3-targeted cancer immunotherapy.
Results: TIM-3 has gained significant importance to be a potential biomarker in cancer immunotherapy. It has been shown that blockade with checkpoint inhibitors promotes anti-tumor immunity and inhibits tumor growth in several preclinical tumor models.
Conclusion: TIM-3 is an immune regulating molecule expressed on several cell types, including IFNγ-producing T-cells, FoxP3+ Treg cells, and innate immune cells. The roles of TIM-3 in immunosuppression support its merit as a target for cancer immunotherapy.
Keywords: T-cell immunoglobulin, cancer, Galectin-9, TIM-3, receptor, ligand.
[http://dx.doi.org/10.1038/nri1111] [PMID: 12776205]
[http://dx.doi.org/10.1111/j.0105-2896.2010.00903.x] [PMID: 20536563]
[http://dx.doi.org/10.1177/0194599818774560] [PMID: 29759032]
[http://dx.doi.org/10.1016/j.imlet.2011.08.003] [PMID: 21911007]
[http://dx.doi.org/10.2147/OTT.S170385] [PMID: 30410357]
[http://dx.doi.org/10.1126/science.1148536] [PMID: 18006747]
[http://dx.doi.org/10.1002/eji.200939274] [PMID: 19676072]
[http://dx.doi.org/10.1038/415536a] [PMID: 11823861]
[http://dx.doi.org/10.2500/aap.2013.34.3646] [PMID: 23406933]
[http://dx.doi.org/10.1084/jem.20150388] [PMID: 26598760]
[http://dx.doi.org/10.1016/j.immuni.2007.11.011] [PMID: 18082433]
[http://dx.doi.org/10.1016/j.immuni.2007.11.008] [PMID: 18083575]
[http://dx.doi.org/10.4049/jimmunol.0903059] [PMID: 20083673]
[PMID: 1545126]
[http://dx.doi.org/10.1084/jem.182.5.1597] [PMID: 7595231]
[http://dx.doi.org/10.1038/nri957] [PMID: 12461569]
[http://dx.doi.org/10.1074/jbc.272.9.6078] [PMID: 9038233]
[http://dx.doi.org/10.3389/fonc.2018.00086] [PMID: 29644214]
[http://dx.doi.org/10.1155/2010/683875] [PMID: 21127709]
[http://dx.doi.org/10.1073/pnas.1434299100] [PMID: 12920180]
[http://dx.doi.org/10.4049/jimmunol.1102807] [PMID: 22634623]
[http://dx.doi.org/10.1038/ni1271] [PMID: 16286920]
[http://dx.doi.org/10.3389/fimmu.2019.01594] [PMID: 31354733]
[http://dx.doi.org/10.1371/journal.ppat.1003253] [PMID: 23555261]
[http://dx.doi.org/10.1038/s41577-019-0224-6] [PMID: 31676858]
[http://dx.doi.org/10.1038/s41467-021-21099-2] [PMID: 33547304]
[http://dx.doi.org/10.1126/science.316.5831.1556] [PMID: 17569836]
[http://dx.doi.org/10.1080/2162402X.2018.1438109] [PMID: 29872582]
[http://dx.doi.org/10.1038/ni.2376] [PMID: 22842346]
[http://dx.doi.org/10.3892/mmr.2016.6003] [PMID: 27959427]
[http://dx.doi.org/10.1177/44.1.8543780] [PMID: 8543780]
[http://dx.doi.org/10.1038/nature13848] [PMID: 25363763]
[http://dx.doi.org/10.1146/annurev.ph.57.030195.003135] [PMID: 7778880]
[http://dx.doi.org/10.1016/0016-5085(94)90057-4] [PMID: 8020672]
[http://dx.doi.org/10.1097/00006676-200304000-00022] [PMID: 12657964]
[http://dx.doi.org/10.1038/modpathol.3800445] [PMID: 15976813]
[http://dx.doi.org/10.1136/jcp.56.5.378] [PMID: 12719460]
[http://dx.doi.org/10.1016/S0090-4295(03)00560-0] [PMID: 14550470]
[http://dx.doi.org/10.1177/44.10.8813081] [PMID: 8813081]
[http://dx.doi.org/10.1177/002215549704501111] [PMID: 9358856]
[http://dx.doi.org/10.1093/nar/28.1.231] [PMID: 10592234]
[http://dx.doi.org/10.1016/j.gene.2007.12.014] [PMID: 18242885]
[http://dx.doi.org/10.1371/journal.pone.0030676] [PMID: 22363469]
[http://dx.doi.org/10.1182/blood-2011-06-360321] [PMID: 22323453]
[http://dx.doi.org/10.1007/s13238-015-0220-y] [PMID: 26487564]
[http://dx.doi.org/10.1007/s00281-003-0141-3] [PMID: 15007635]
[http://dx.doi.org/10.1038/nature06307] [PMID: 17960135]
[http://dx.doi.org/10.1038/s41598-018-35754-0] [PMID: 30504845]
[http://dx.doi.org/10.1016/S0022-2836(84)71582-8] [PMID: 7932691]
[http://dx.doi.org/10.1006/jmbi.1996.0726] [PMID: 9020980]
[http://dx.doi.org/10.1016/j.immuni.2007.01.016] [PMID: 17363302]
[http://dx.doi.org/10.1111/imr.12520] [PMID: 28258697]
[http://dx.doi.org/10.1158/0008-5472.CAN-11-1487] [PMID: 22009533]
[http://dx.doi.org/10.2174/1872214811307020006] [PMID: 23514536]
[http://dx.doi.org/10.7314/APJCP.2012.13.6.2503] [PMID: 22938412]
[http://dx.doi.org/10.1158/0008-5472.CAN-12-1260] [PMID: 23108139]
[http://dx.doi.org/10.1080/07357900701837051] [PMID: 18584353]
[PMID: 19691922]
[http://dx.doi.org/10.1002/ijc.10436] [PMID: 12115481]
[http://dx.doi.org/10.7314/APJCP.2014.15.5.2145] [PMID: 24716948]
[http://dx.doi.org/10.1016/S0002-9440(10)61121-2] [PMID: 12000726]
[http://dx.doi.org/10.1074/jbc.272.10.6416] [PMID: 9045665]
[http://dx.doi.org/10.3892/ijo.2014.2494] [PMID: 24919464]
[http://dx.doi.org/10.1371/journal.pone.0081799] [PMID: 24339967]
[http://dx.doi.org/10.4049/jimmunol.170.7.3631] [PMID: 12646627]
[http://dx.doi.org/10.1038/ni988] [PMID: 14556006]
[http://dx.doi.org/10.1016/S0065-2776(06)91006-2] [PMID: 16938542]
[http://dx.doi.org/10.1111/cas.13723] [PMID: 30187676]
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1038] [PMID: 30042205]
[http://dx.doi.org/10.1172/JCI43127] [PMID: 21084749]
[http://dx.doi.org/10.1084/jem.20100643] [PMID: 20819927]
[http://dx.doi.org/10.1182/blood-2010-10-310425] [PMID: 21385853]
[http://dx.doi.org/10.1084/jem.20100637] [PMID: 20819923]
[http://dx.doi.org/10.1158/0008-5472.CAN-11-0096] [PMID: 21430066]
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0039] [PMID: 24795351]
[http://dx.doi.org/10.1158/1078-0432.CCR-17-1350] [PMID: 29712685]
[http://dx.doi.org/10.1007/s13277-015-4237-x] [PMID: 26482613]
[http://dx.doi.org/10.4161/onci.23849] [PMID: 23734331]
[http://dx.doi.org/10.1155/2016/1720827] [PMID: 27298831]
[http://dx.doi.org/10.1186/s13046-018-0713-7] [PMID: 29506555]
[PMID: 29276179]
[http://dx.doi.org/10.3233/CBM-181368] [PMID: 29843224]
[http://dx.doi.org/10.1038/s41598-017-09484-8] [PMID: 28827755]
[http://dx.doi.org/10.1007/s00595-016-1305-9] [PMID: 26801344]
[http://dx.doi.org/10.1038/nri3790]
[http://dx.doi.org/10.1158/1078-0432.CCR-18-4142] [PMID: 31053602]
[http://dx.doi.org/10.18632/oncotarget.8157] [PMID: 27008699]
[http://dx.doi.org/10.1007/s13277-012-0610-1] [PMID: 23359271]
[http://dx.doi.org/10.1007/s11033-012-1862-y] [PMID: 22733499]
[http://dx.doi.org/10.1007/s00262-010-0910-5] [PMID: 20811886]
[http://dx.doi.org/10.18632/oncotarget.9665] [PMID: 27248321]
[http://dx.doi.org/10.4155/fsoa-2017-0121] [PMID: 29796301]
[http://dx.doi.org/10.1186/s40064-016-3339-2] [PMID: 27733989]
[http://dx.doi.org/10.1097/MD.0000000000005749] [PMID: 28033288]
[http://dx.doi.org/10.1016/j.ygyno.2020.07.012] [PMID: 32694063]
[http://dx.doi.org/10.3892/ol.2018.8697] [PMID: 29963183]
[http://dx.doi.org/10.7314/APJCP.2013.14.6.3897] [PMID: 23886204]
[http://dx.doi.org/10.1002/jso.24012] [PMID: 26265374]
[http://dx.doi.org/10.1371/journal.pone.0053834] [PMID: 23335978]
[http://dx.doi.org/10.1136/gutjnl-2014-307671] [PMID: 25608525]
[http://dx.doi.org/10.1007/s00262-018-2225-x] [PMID: 30128737]
[http://dx.doi.org/10.1038/ncomms10501] [PMID: 26883990]
[http://dx.doi.org/10.1080/2162402X.2016.1261779] [PMID: 28197389]
[http://dx.doi.org/10.1038/ni.2396] [PMID: 22910384]
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0156] [PMID: 25783986]
[http://dx.doi.org/10.4149/neo_2014_006] [PMID: 24195506]
[http://dx.doi.org/10.1097/00000478-200305000-00005] [PMID: 12717246]
[http://dx.doi.org/10.1016/j.stem.2010.11.014] [PMID: 21112565]
[http://dx.doi.org/10.1073/pnas.1100551108] [PMID: 21383193]
[http://dx.doi.org/10.1016/j.ccell.2017.11.019] [PMID: 29316433]
[http://dx.doi.org/10.1016/j.cellimm.2017.01.001] [PMID: 28110884]
[http://dx.doi.org/10.1016/j.ccell.2018.03.012] [PMID: 29634943]
[http://dx.doi.org/10.1172/JCI59806] [PMID: 22426209]
[http://dx.doi.org/10.1084/jem.20081398] [PMID: 19001139]
[http://dx.doi.org/10.1136/esmoopen-2019-000497] [PMID: 31275616]