Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy

References

• Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody promotes T cell IFN-{gamma}-mediated anti-tumor immunity and suppresses established tumors. Cancer Res. 2011;71:3540–51. doi:10.1158/0008-5472.CAN-11-0096. PMID:21430066
   PubMed Web of Science ®Google Scholar
• Dardalhon V, Anderson AC, Karman J, Apetoh L, Chandwaskar R, Lee DH, Cornejo M, Nishi N, Yamauchi A, Quintana FJ, et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J Immunol. 2010;185:1383–92. doi:10.4049/jimmunol.0903275. PMID:20574007
   PubMed Web of Science ®Google Scholar
• 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;207:2187–94. doi:10.1084/jem.20100643. PMID:20819927
   PubMed Web of Science ®Google Scholar
• Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM. 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;207:2175–86. doi:10.1084/jem.20100637. PMID:20819923
   PubMed Web of Science ®Google Scholar
• Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501. doi:10.1038/ncomms10501. PMID:26883990
   PubMed Web of Science ®Google Scholar
• Shayan G, Srivastava R, Li J, Schmitt N, Kane LP, Ferris RL. Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3 K-Akt pathway in head and neck cancer. Oncoimmunology. 2017;6:e1261779. doi:10.1080/2162402X.2016.1261779. PMID:28197389
   PubMed Web of Science ®Google Scholar
• Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–52. doi:10.1038/ni1271. PMID:16286920
   PubMed Web of Science ®Google Scholar
• Cao E, Zang X, Ramagopal UA, Mukhopadhaya A, Federov A, Federov E, Zencheck WD, Lary JW, Cole JL, Deng H, et al. T cell immunoglobulin mucin-3 crystal structure reveals a novel ligand binding surface. Immunity. 2007;26:311–21. doi:10.1016/j.immuni.2007.01.016. PMID:17363302
   PubMed Web of Science ®Google Scholar
• Santiago C, Ballestros A, Tami C, Martinez-Munoz L, Kaplan GG, Casanovas JM. Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity. 2007;26:299–310. doi:10.1016/j.immuni.2007.01.014. PMID:17363299
   PubMed Web of Science ®Google Scholar
• Santiago C, Ballestros A, Martinez-Munoz L, Mellado M, Kaplan GG, Freeman GJ, Casanovas JM. Structures of T Cell Immunoglobulin Mucin Protein 4 show a metal-ion-dependent ligand binding site where phosphatidylserine binds. Immunity. 2007;27:941–5. doi:10.1016/j.immuni.2007.11.008. PMID:18083575
   PubMed Web of Science ®Google Scholar
• DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, et al. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol. 2010;184:1918–30. doi:10.4049/jimmunol.0903059. PMID:20083673
   PubMed Web of Science ®Google Scholar
• Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, 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;13:832–42.
   PubMed Web of Science ®Google Scholar
• Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A, Dougan SK, Petersen BS, Melum E, Pertel T, et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2015;517:386–90. doi:10.1038/nature13848. PMID:25363763
   PubMed Web of Science ®Google Scholar
• Sakuishi K, Ngiow SF, Sullivan JM, Teng MWL, Kuchroo VK, Smyth MJ, Anderson AC. TIM3+FOXP3+ regulatory Tcells are tissue-specific promoters of T-cell dysfunction in cancer. OncoImmunology. 2013;2:e23849. doi:10.4161/onci.23849. PMID:23734331
   PubMed Web of Science ®Google Scholar
• Burns-Hamuro LL, Hamuro Y, Kim JS, Sigala P, Fayos R, Stranz DD, Jennings PA, Taylor SS, Woods VL, Jr. Distinct interaction modes of an AKAP bound to two regulatory subunit isoforms of protein kinase A revealed by amide hydrogen/deuterium exchange. Protein Sci. 2005;14:2982–92. doi:10.1110/ps.051687305. PMID:16260760
   PubMed Web of Science ®Google Scholar
• Rangachari M, Zhu C, Sakuishi K, Xiao S, Karman J, Chen A, Angin M, Wakeham A, Greenfield EA, Sobel RA, et al. Bat3 protects T cell responses by repressing Tim-3-mediated exhaustion and death. Nat Med. 2012;18:1394–400. doi:10.1038/nm.2871. PMID:22863785
   PubMed Web of Science ®Google Scholar
• Lee J, Su EW, Zhu C, Hainline S, Phuah J, Moroco JA, Smithgall TE, Kuchroo VK, Kane LP. Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol Cell Biol. 2011;31:3963–74. doi:10.1128/MCB.05297-11. PMID:21807895
   PubMed Web of Science ®Google Scholar
• Davidson D, Schraven B, Veillette A. PAG-associated FynT regulates calcium signaling and promotes anergy in T lymphocytes. Mol Cell Biol. 2007;27:1960–73. doi:10.1128/MCB.01983-06. PMID:17210649
   PubMed Web of Science ®Google Scholar
• Clayton KL, Haaland MS, Douglas-Vail MB, Mujib S, Chew GM, Ndhlovu LC, Ostrowski MA. T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases. J Immunol. 2014;192:782–91. doi:10.4049/jimmunol.1302663. PMID:24337741
   PubMed Web of Science ®Google Scholar
• Clayton KL, Douglas-Vail MB, Nur-ur Rahman AK, Medcalf KE, Xie IY, Chew GM, Tandon R, Lanteri MC, Norris PJ, Deeks SG, et al. Soluble T cell immunoglobulin mucin domain 3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression. J Virol. 2015;89:3723–36. doi:10.1128/JVI.00006-15. PMID:25609823
   PubMed Web of Science ®Google Scholar
• Moller-Hackbarth K, Dewitz C, Schweigert O, Trad A, Garbers C, Rose-John S, Scheller J. A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3). J Biol Chem. 2013;288:34529–44.
   PubMed Web of Science ®Google Scholar
• Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol. 2003;4:1102–10. doi:10.1038/ni988. PMID:14556006
   PubMed Web of Science ®Google Scholar
• Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutierrez-Ramos JC, Coyle AJ, Strom TB. TIM-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat. Immunol. 2003;4:1093–101. doi:10.1038/ni987. PMID:14556005
   PubMed Web of Science ®Google Scholar
• Park IH, Venable JD, Steckler C, Cellitti SE, Lesley SA, Spraggon G, Brock A. Estimation of Hydrogen-Exchange Protection Factors from MD Simulation Based on Amide Hydrogen Bonding Analysis. J Chem Inf Model. 2015;55:1914–25. doi:10.1021/acs.jcim.5b00185. PMID:26241692
   PubMed Web of Science ®Google Scholar