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Tim-3 Regulation of Cancer Immunity

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Tumor-Induced Immune Suppression
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Abstract

Chronic unrelenting immune responses can lead to immunopathology that can be fatal. Consequently, the immune system has evolved both molecular and cellular mechanisms that serve to contract active immune responses and restore immune homeostasis. Molecular mechanisms include the upregulation of inhibitory or immune checkpoint receptors on T cells post activation. Cellular mechanisms include regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) that suppress active T-cell responses. Unfortunately, all of these mechanisms have been co-opted in cancer to suppress the generation of productive antitumor T-cell responses. In tumor-bearing hosts, the sustained expression of immune checkpoint receptors on T cells results in T-cell dysfunction or exhaustion. Moreover, MDSCs expand to large numbers in tumor-bearing hosts and the tumor microenvironment promotes Tregs. The inhibitory receptor T-cell immunoglobulin and mucin domain 3 (Tim-3) has a role in each of these mechanisms of immune suppression, thus highlighting the value of Tim-3 as a target for anticancer immunotherapy. Here, we discuss the role of Tim-3 in each of these mechanisms and the implications for the development of agents that target Tim-3 for cancer treatment.

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References

  1. Anderson AC, Anderson DE, Bregoli L et al (2007) Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318:1141–1143

    Article  CAS  PubMed  Google Scholar 

  2. Ansell SM, Geyer SM, Maurer MJ et al (2006) Randomized phase II study of interleukin-12 in combination with rituximab in previously treated non-Hodgkin’s lymphoma patients. Clin Cancer Res 12:6056–6063

    Article  CAS  PubMed  Google Scholar 

  3. Baghdadi M, Nagao H, Yoshiyama H et al (2012) Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas. Cancer Immunol Immunother 62:629–37.

    Article  PubMed  Google Scholar 

  4. Baitsch L, Baumgaertner P, Devevre E et al (2011) Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients. J Clin Invest 121:2350–2360

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Barber DL, Wherry EJ, Masopust D et al (2006) Restoring function in exhausted CD8T cells during chronic viral infection. Nature 439:682–687

    Article  CAS  PubMed  Google Scholar 

  6. Blackburn SD, Shin H, Haining WN et al (2009) Coregulation of CD8+T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Blackburn SD, Wherry EJ (2007) IL-10, T cell exhaustion and viral persistence. Trends Microbiol 15:143–146

    Article  CAS  PubMed  Google Scholar 

  8. Boni C, Fisicaro P, Valdatta C et al (2007) Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 81:4215–4225

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Brown KE, Freeman GJ, Wherry EJ et al (2010) Role of PD-1 in regulating acute infections. Curr Opin Immunol 22:397–401

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Campbell DJ, Koch MA (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11:119–130

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Chemnitz JM, Parry RV, Nichols KE et al (2004) SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173:945–954

    CAS  PubMed  Google Scholar 

  12. Chiba S, Baghdadi M, Akiba H et al (2012) Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol 13:832–842

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Cipolletta D, Feuerer M, Li A et al (2012) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486:549–553

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Curran MA, Montalvo W, Yagita H et al (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 107:4275–4280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Dardalhon V, Anderson AC, Karman J et al (2010) Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+ Ly-6G+ myeloid cells. J Immunol 185:1383–1392

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Day CL, Kaufmann DE, Kiepiela P et al (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–354

    Article  CAS  PubMed  Google Scholar 

  17. DeKruyff RH, Bu X, Ballesteros A et al (2010) T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol 184:1918–1930

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Del Vecchio M, Bajetta, Canova S et al (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677–4685

    Article  CAS  PubMed  Google Scholar 

  19. Feuerer M, Herrero L, Cipolletta D et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Fourcade J, Sun Z, Benallaoua M et al (2010) Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 207:2175–2186

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Francisco LM, Sage PT, Sharpe AH (2010) The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 236:219–2142

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Gao X, Zhu Y, Li G et al (2012) TIM-3 Expression Characterizes Regulatory T Cells in Tumor Tissues and Is Associated with Lung Cancer Progression. PLoS One 7:e30676

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Golden-Mason L, Palmer BE, Kassam N et al (2009) Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 83:9122–9130

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Gupta S, Thornley TB, Gao W et al (2012) Allograft rejection is restrained by short-lived TIM-3+ PD-1+ Foxp3+ Tregs. J Clin Invest 122:2395–2404

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Hodi FS, Butler M, Oble DA et al (2008) Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A 105:3005–3010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Huang CT, Workman CJ, Flies D et al (2004) Role of LAG-3 in regulatory T cells. Immunity 21:503–513

    Article  CAS  PubMed  Google Scholar 

  29. Huang X, Bai X, Cao Y et al (2010) Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J Exp Med 207:505–520

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Jan M, Chao MP, Cha AC et al (2011) Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci U S A 108:5009–5014

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Jin HT, Anderson AC, Tan WG et al (2010) Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 107:14733–14738

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Jones RB, Ndhlovu LC, Barbour JD et al (2008) Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med 205:2763–2779

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Ju Y, Hou N, Zhang XN et al (2009) Blockade of Tim-3 pathway ameliorates interferon-gamma production from hepatic CD8+ T cells in a mouse model of hepatitis B virus infection. Cell Mol Immunol 6:35–43

    Article  CAS  PubMed  Google Scholar 

  34. Kikushige Y, Shima T, Takayanagi S et al (2010) TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 7:708–717

    Article  CAS  PubMed  Google Scholar 

  35. Kim PS, Ahmed R (2010) Features of responding T cells in cancer and chronic infection. Curr Opin Immunol 22:223–230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Koch MA, Tucker-Heard G, Perdue NR et al (2009) The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10:595–602

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Krebs P, Scandella E, Odermatt B et al (2005) Rapid functional exhaustion and deletion of CTL following immunization with recombinant adenovirus. J Immunol 174:4559–4566

    CAS  PubMed  Google Scholar 

  38. Lee J, Su EW, Zhu C et al (2011) Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol Cell Biol 31:3963–3974

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Lee MJ, Woo MY, Heo YM et al (2010) The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine. Biochem Biophys Res Commun 402:88–93

    Article  CAS  PubMed  Google Scholar 

  40. Li B, VanRoey M, Wang C et al (2009) Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor–secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin Cancer Res 15:1623–1634

    Article  CAS  PubMed  Google Scholar 

  41. McMahan RH, Golden-Mason L, Nishimura MI et al (2011) Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest 120:4546–4557

    Article  Google Scholar 

  42. Monney L, Sabatos CA, Gaglia JL et al (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415:536–541

    Article  CAS  PubMed  Google Scholar 

  43. Mueller SN, Ahmed R (2009) High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 106:8623–8628

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Nakayama M, Akiba H, Takeda K et al (2009) Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113:3821–3830

    Article  CAS  PubMed  Google Scholar 

  45. Ngiow SF, von Scheidt B, Akiba H et al (2011) Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res 71:3540–3551

    Article  CAS  PubMed  Google Scholar 

  46. Nishimura H, Honjo T, Minato N (2000) Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med 191:891–898

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Nishimura H, Nose M, Hiai H et al (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151

    Article  CAS  PubMed  Google Scholar 

  48. Parry RV, Chemnitz JM, Frauwirth KA et al (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Petrovas C, Casazza JP, Brenchley JM et al (2006) PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203:2281–2292

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Radziewicz H, Ibegbu CC, Fernandez ML et al (2007) Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 81:2545–2553

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Rangachari M, Zhu C, Sakuishi K et al (2012) Bat3 Protects T cell Responses by Repressing Tim-3-Mediated Exhaustion and Death. Nat Med 18:1394–1400

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Sabatos CA, Chakravarti S, Cha E et al (2003) Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 4:1102–1110

    Article  CAS  PubMed  Google Scholar 

  53. Sakuishi K, Apetoh L, Sullivan JM et al (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207:2187–2194

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Sansom DM, Walker LS (2006) The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol Rev 212:131–148

    Article  CAS  PubMed  Google Scholar 

  55. Takamura S, Tsuji-Kawahara S, Yagita H et al (2010) Premature terminal exhaustion of Friend virus-specific effector CD8+ T cells by rapid induction of multiple inhibitory receptors. J Immunol 184:4696–4707

    Article  CAS  PubMed  Google Scholar 

  56. Tesniere A, Schlemmer F, Boige V et al (2010) Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29:482–491

    Article  CAS  PubMed  Google Scholar 

  57. Tivol EA, Borriello F, Schweitzer AN et al (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547

    Article  CAS  PubMed  Google Scholar 

  58. Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Trautmann L, Janbazian L, Chomont N et al (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12:1198–1202

    Article  CAS  PubMed  Google Scholar 

  60. Urbani S, Amadei B, Tola D et al (2006) PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 80:11398–11403

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190:355–366.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Waterhouse P, Penninger JM, Timms E et al (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988

    Article  CAS  PubMed  Google Scholar 

  63. Wherry EJ (2011) T cell exhaustion. Nat Immunol 131:492–499

    Article  Google Scholar 

  64. Wherry EJ, Ha SJ, Kaech SM et al (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:670–684

    Article  CAS  PubMed  Google Scholar 

  65. Wilson JJ, Pack CD, Lin E et al (2012) CD8 T cells recruited early in mouse polyomavirus infection undergo exhaustion. J Immunol 188:4340–4348

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Wu FH, Yuan Y, Li D et al (2010) Endothelial cell-expressed Tim-3 facilitates metastasis of melanoma cells by activating the NF-kappaB pathway. Oncol Rep 24:693–699

    Article  CAS  PubMed  Google Scholar 

  67. Yang ZZ, Grote DM, Ziesmer SC et al (2012) IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J Clin Invest 122:1271–1282

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Yi JS, Cox MA, Zajac AJ (2010) T-cell exhaustion: characteristics, causes and conversion. Immunology 129:474–481

    Article  CAS  PubMed  Google Scholar 

  69. Zhang Y, Ma CJ, Wang JM et al (2012) Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes. J Leukoc Biol 91:189–196

    Article  CAS  PubMed  Google Scholar 

  70. Zheng Y, Chaudhry A, Kas A et al (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458:351–356

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Zheng Y, Zha Y, Gajewski TF (2008) Molecular regulation of T-cell anergy. EMBO Rep 9:50–55

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Zhou Q, Munger ME, Veenstra RG et al (2011) Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117:4501–4510

    Article  CAS  PubMed  Google Scholar 

  73. Zhu C, Anderson AC, Schubart A et al (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6:1245–1252

    Article  CAS  PubMed  Google Scholar 

  74. Zhuang X, Zhang X, Xia X et al (2012) Ectopic expression of TIM-3 in lung cancers: a potential independent prognostic factor for patients with NSCLC. Am J Clin Pathol 137:978–985

    Article  CAS  PubMed  Google Scholar 

  75. Imaizumi T, Kumagai M, Sasaki N et al. (2002) Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells. J Leukoc Biol 72:486–491

    Google Scholar 

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Correspondence to Ana C. Anderson .

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Sakuishi, K., Anderson, A. (2014). Tim-3 Regulation of Cancer Immunity. In: Gabrilovich, D., Hurwitz, A. (eds) Tumor-Induced Immune Suppression. Springer, New York, NY. https://doi.org/10.1007/978-1-4899-8056-4_8

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