Skip to main content

Advertisement

Log in

Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology

  • Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Tumor-infiltrating lymphocytes (TIL) are one of the representative components of host antitumor immune responses. Both the quality and quantity of TIL determine the effect of the antitumor immune reaction. Previous studies have indicated that patients with cancers showing massive infiltration of CD8+ T cells generally have a better clinical outcome. Conversely, patients with marked infiltration of immunosuppressive cells such as regulatory T cells tend to have a worse prognosis for several types of cancer. The density and distribution of TIL are also strongly affected by the trafficking route. Tumor-associated blood vessels in various cancers are structurally and functionally abnormal, and such abnormal vessels reportedly become an obstacle for infiltration of immune effector cells into tumors. Recently, understanding of the molecular mechanisms of lymphocyte trafficking has progressed rapidly. This review focuses on the mechanisms of lymphocyte trafficking to tumor cells and also discusses the importance of blood vessel for TIL trafficking, especially in relation to hepatocarcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. von Andrian UH, Mackay CR (2000) T-cell function and migration. Two sides of the same coin. N Engl J Med 343:1020–1034

    Article  Google Scholar 

  2. Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272:60–66

    Article  CAS  PubMed  Google Scholar 

  3. Friedl P, Weigelin B (2008) Interstitial leukocyte migration and immune function. Nat Immunol 9:960–969

    Article  CAS  PubMed  Google Scholar 

  4. Luster AD, Alon R, von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6:1182–1190

    Article  CAS  PubMed  Google Scholar 

  5. Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  CAS  PubMed  Google Scholar 

  6. Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213

    Article  CAS  PubMed  Google Scholar 

  7. Wilke CM, Wu K, Zhao E et al (2010) Prognostic significance of regulatory T cells in tumor. Int J Cancer 127:748–758

    CAS  PubMed  Google Scholar 

  8. Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307

    Article  CAS  PubMed  Google Scholar 

  9. Curiel TJ (2008) Regulatory T cells and treatment of cancer. Curr Opin Immunol 20:241–246

    Article  CAS  PubMed  Google Scholar 

  10. Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314

    Article  CAS  PubMed  Google Scholar 

  11. Ley K, Laudanna C, Cybulsky MI et al (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7:678–689

    Article  CAS  PubMed  Google Scholar 

  12. Nourshargh S, Hordijk PL, Sixt M (2010) Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nat Rev Mol Cell Biol 11:366–378

    Article  CAS  PubMed  Google Scholar 

  13. Lowe JB (2001) Glycosylation, immunity, and autoimmunity. Cell 104:809–812

    Article  CAS  PubMed  Google Scholar 

  14. Rosen SD (2004) Ligands for L-selectin: homing, inflammation, and beyond. Annu Rev Immunol 22:129–156

    Article  CAS  PubMed  Google Scholar 

  15. Fukuda M, Hiraoka N, Yeh JC (1999) C-type lectins and sialyl Lewis X oligosaccharides. Versatile roles in cell–cell interaction. J Cell Biol 147:467–470

    Article  CAS  PubMed  Google Scholar 

  16. Yeh JC, Hiraoka N, Petryniak B et al (2001) Novel sulfated lymphocyte homing receptors and their control by a Core1 extension beta 1,3-N-acetylglucosaminyltransferase. Cell 105:957–969

    Article  CAS  PubMed  Google Scholar 

  17. McEver RP (2002) Selectins: lectins that initiate cell adhesion under flow. Curr Opin Cell Biol 14:581–586

    Article  CAS  PubMed  Google Scholar 

  18. Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129:865–877

    Article  CAS  PubMed  Google Scholar 

  19. Cernuda-Morollon E, Ridley AJ (2006) Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells. Circ Res 98:757–767

    Article  CAS  PubMed  Google Scholar 

  20. Arnaout MA, Mahalingam B, Xiong JP (2005) Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 21:381–410

    Article  CAS  PubMed  Google Scholar 

  21. Ridley AJ, Schwartz MA, Burridge K et al (2003) Cell migration: integrating signals from front to back. Science 302:1704–1709

    Article  CAS  PubMed  Google Scholar 

  22. Barreiro O, de la Fuente H, Mittelbrunn M et al (2007) Functional insights on the polarized redistribution of leukocyte integrins and their ligands during leukocyte migration and immune interactions. Immunol Rev 218:147–164

    Article  CAS  PubMed  Google Scholar 

  23. Shulman Z, Shinder V, Klein E et al (2009) Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin. Immunity 30:384–396

    Article  CAS  PubMed  Google Scholar 

  24. Carman CV, Springer TA (2004) A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 167:377–388

    Article  CAS  PubMed  Google Scholar 

  25. Barreiro O, Yanez-Mo M, Serrador JM et al (2002) Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 157:1233–1245

    Article  CAS  PubMed  Google Scholar 

  26. Feng D, Nagy JA, Pyne K et al (1998) Neutrophils emigrate from venules by a transendothelial cell pathway in response to FMLP. J Exp Med 187:903–915

    Article  CAS  PubMed  Google Scholar 

  27. Muller WA (2003) Leukocyte–endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 24:327–334

    CAS  PubMed  Google Scholar 

  28. Vestweber D (2002) Regulation of endothelial cell contacts during leukocyte extravasation. Curr Opin Cell Biol 14:587–593

    Article  CAS  PubMed  Google Scholar 

  29. Woodfin A, Voisin MB, Imhof BA et al (2009) Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1. Blood 113:6246–6257

    Article  CAS  PubMed  Google Scholar 

  30. Millan J, Hewlett L, Glyn M et al (2006) Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nat Cell Biol 8:113–123

    Article  CAS  PubMed  Google Scholar 

  31. Engelhardt B, Wolburg H (2004) Mini-review: transendothelial migration of leukocytes: through the front door or around the side of the house? Eur J Immunol 34:2955–2963

    Article  CAS  PubMed  Google Scholar 

  32. Cinamon G, Shinder V, Shamri R et al (2004) Chemoattractant signals and beta 2 integrin occupancy at apical endothelial contacts combine with shear stress signals to promote transendothelial neutrophil migration. J Immunol 173:7282–7291

    CAS  PubMed  Google Scholar 

  33. Rowe RG, Weiss SJ (2008) Breaching the basement membrane: who, when and how? Trends Cell Biol 18:560–574

    Article  CAS  PubMed  Google Scholar 

  34. Leppert D, Waubant E, Galardy R et al (1995) T cell gelatinases mediate basement membrane transmigration in vitro. J Immunol 154:4379–4389

    CAS  PubMed  Google Scholar 

  35. Mydel P, Shipley JM, Adair-Kirk TL et al (2008) Neutrophil elastase cleaves laminin-332 (laminin-5) generating peptides that are chemotactic for neutrophils. J Biol Chem 283:9513–9522

    Article  CAS  PubMed  Google Scholar 

  36. Friedl P, Entschladen F, Conrad C et al (1998) CD4+ T lymphocytes migrating in three-dimensional collagen lattices lack focal adhesions and utilize beta1 integrin-independent strategies for polarization, interaction with collagen fibers and locomotion. Eur J Immunol 28:2331–2343

    Article  CAS  PubMed  Google Scholar 

  37. Lammermann T, Bader BL, Monkley SJ et al (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453:51–55

    Article  PubMed  CAS  Google Scholar 

  38. Boissonnas A, Fetler L, Zeelenberg IS et al (2007) In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J Exp Med 204:345–356

    Article  CAS  PubMed  Google Scholar 

  39. Breart B, Lemaitre F, Celli S et al (2008) Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J Clin Invest 118:1390–1397

    Article  CAS  PubMed  Google Scholar 

  40. Mrass P, Takano H, Ng LG et al (2006) Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J Exp Med 203:2749–2761

    Article  CAS  PubMed  Google Scholar 

  41. Le Floc’h A, Jalil A, Vergnon I et al (2007) Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J Exp Med 204:559–570

    Article  PubMed  CAS  Google Scholar 

  42. Thomsen AR, Nansen A, Madsen AN et al (2003) Regulation of T cell migration during viral infection: role of adhesion molecules and chemokines. Immunol Lett 85:119–127

    Article  CAS  PubMed  Google Scholar 

  43. Naito Y, Saito K, Shiiba K et al (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494

    CAS  PubMed  Google Scholar 

  44. Wada Y, Nakashima O, Kutami R et al (1998) Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 27:407–414

    Article  CAS  PubMed  Google Scholar 

  45. Budhu S, Loike JD, Pandolfi A et al (2010) CD8+ T cell concentration determines their efficiency in killing cognate antigen-expressing syngeneic mammalian cells in vitro and in mouse tissues. J Exp Med 207:223–235

    Article  CAS  PubMed  Google Scholar 

  46. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360

    Article  CAS  PubMed  Google Scholar 

  47. Johansson M, Denardo DG, Coussens LM (2008) Polarized immune responses differentially regulate cancer development. Immunol Rev 222:145–154

    Article  CAS  PubMed  Google Scholar 

  48. Kemp RA, Ronchese F (2001) Tumor-specific Tc1, but not Tc2, cells deliver protective antitumor immunity. J Immunol 167:6497–6502

    CAS  PubMed  Google Scholar 

  49. Stockinger B, Veldhoen M, Martin B (2007) Th17 T cells: linking innate and adaptive immunity. Semin Immunol 19:353–361

    Article  CAS  PubMed  Google Scholar 

  50. Bettelli E, Carrier Y, Gao W et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  CAS  PubMed  Google Scholar 

  51. Kimura A, Naka T, Nohara K et al (2008) Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci USA 105:9721–9726

    Article  CAS  PubMed  Google Scholar 

  52. Ouyang W, Kolls JK, Zheng Y (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28:454–467

    Article  CAS  PubMed  Google Scholar 

  53. Bettelli E, Korn T, Oukka M et al (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–1057

    Article  CAS  PubMed  Google Scholar 

  54. Miyahara Y, Odunsi K, Chen W et al (2008) Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci USA 105:15505–15510

    Article  CAS  PubMed  Google Scholar 

  55. Kryczek I, Banerjee M, Cheng P et al (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114:1141–1149

    Article  CAS  PubMed  Google Scholar 

  56. Zhang JP, Yan J, Xu J et al (2009) Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 50:980–989

    Article  CAS  PubMed  Google Scholar 

  57. Wang L, Yi T, Kortylewski M et al (2009) IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 206:1457–1464

    Article  CAS  PubMed  Google Scholar 

  58. Kryczek I, Wei S, Szeliga W et al (2009) Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood 114:357–359

    Article  CAS  PubMed  Google Scholar 

  59. Muranski P, Boni A, Antony PA et al (2008) Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112:362–373

    Article  CAS  PubMed  Google Scholar 

  60. Rudensky AY, Gavin M, Zheng Y (2006) FOXP3 and NFAT: partners in tolerance. Cell 126:253–256

    Article  CAS  PubMed  Google Scholar 

  61. Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  CAS  PubMed  Google Scholar 

  62. Sakaguchi S, Miyara M, Costantino CM et al (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500

    Article  CAS  PubMed  Google Scholar 

  63. Tang Q, Bluestone JA (2008) The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 9:239–244

    Article  CAS  PubMed  Google Scholar 

  64. Hiraoka N, Onozato K, Kosuge T et al (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434

    Article  CAS  PubMed  Google Scholar 

  65. Kobayashi N, Hiraoka N, Yamagami W et al (2007) FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 13:902–911

    Article  CAS  PubMed  Google Scholar 

  66. Salama P, Phillips M, Grieu F et al (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192

    Article  PubMed  Google Scholar 

  67. Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907–1917

    Article  PubMed  Google Scholar 

  68. Ueno Y, Moriyama M, Uchida T et al (2001) Irregular regeneration of hepatocytes is an important factor in the hepatocarcinogenesis of liver disease. Hepatology 33:357–362

    Article  CAS  PubMed  Google Scholar 

  69. Sakamoto M, Hirohashi S, Shimosato Y (1991) Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Hum Pathol 22:172–178

    Article  CAS  PubMed  Google Scholar 

  70. (2009) Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49:658–664

  71. Racanelli V, Rehermann B (2006) The liver as an immunological organ. Hepatology 43:S54–S62

    Article  CAS  PubMed  Google Scholar 

  72. Lee WY, Kubes P (2008) Leukocyte adhesion in the liver: distinct adhesion paradigm from other organs. J Hepatol 48:504–512

    Article  CAS  PubMed  Google Scholar 

  73. Shetty S, Lalor PF, Adams DH (2008) Lymphocyte recruitment to the liver: molecular insights into the pathogenesis of liver injury and hepatitis. Toxicology 254:136–146

    Article  CAS  PubMed  Google Scholar 

  74. Braet F, Wisse E (2002) Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol 1:1

    Article  PubMed  Google Scholar 

  75. Wong J, Johnston B, Lee SS et al (1997) A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Invest 99:2782–2790

    Article  CAS  PubMed  Google Scholar 

  76. Fox-Robichaud A, Kubes P (2000) Molecular mechanisms of tumor necrosis factor alpha-stimulated leukocyte recruitment into the murine hepatic circulation. Hepatology 31:1123–1127

    Article  CAS  PubMed  Google Scholar 

  77. Bonder CS, Norman MU, Swain MG et al (2005) Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1. Immunity 23:153–163

    Article  CAS  PubMed  Google Scholar 

  78. Lalor PF, Sun PJ, Weston CJ et al (2007) Activation of vascular adhesion protein-1 on liver endothelium results in an NF-kappaB-dependent increase in lymphocyte adhesion. Hepatology 45:465–474

    Article  CAS  PubMed  Google Scholar 

  79. Oo YH, Shetty S, Adams DH (2010) The role of chemokines in the recruitment of lymphocytes to the liver. Dig Dis 28:31–44

    Article  PubMed  Google Scholar 

  80. Mantovani A, Savino B, Locati M et al (2010) The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev 21:27–39

    Article  CAS  PubMed  Google Scholar 

  81. Ishida T, Iida S, Akatsuka Y et al (2004) The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma. Clin Cancer Res 10:7529–7539

    Article  CAS  PubMed  Google Scholar 

  82. Ito A, Ishida T, Yano H et al (2009) Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. Cancer Immunol Immunother 58:1195–1206

    Article  CAS  PubMed  Google Scholar 

  83. Yamamoto K, Utsunomiya A, Tobinai K et al (2010) Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia–lymphoma and peripheral T-cell lymphoma. J Clin Oncol 28:1591–1598

    Article  CAS  PubMed  Google Scholar 

  84. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693

    Article  CAS  PubMed  Google Scholar 

  85. Morikawa S, Baluk P, Kaidoh T et al (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000

    PubMed  Google Scholar 

  86. Dirkx AE, Oude Egbrink MG, Kuijpers MJ et al (2003) Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res 63:2322–2329

    CAS  PubMed  Google Scholar 

  87. Buckanovich RJ, Facciabene A, Kim S et al (2008) Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 14:28–36

    Article  CAS  PubMed  Google Scholar 

  88. Hamzah J, Jugold M, Kiessling F et al (2008) Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453:410–414

    Article  CAS  PubMed  Google Scholar 

  89. Shrimali RK, Yu Z, Theoret MR et al (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 70:6171–6180

    Article  CAS  PubMed  Google Scholar 

  90. Matsui O, Kadoya M, Kameyama T et al (1991) Benign and malignant nodules in cirrhotic livers: distinction based on blood supply. Radiology 178:493–497

    CAS  PubMed  Google Scholar 

  91. Hayashi M, Matsui O, Ueda K et al (2002) Progression to hypervascular hepatocellular carcinoma: correlation with intranodular blood supply evaluated with CT during intraarterial injection of contrast material. Radiology 225:143–149

    Article  PubMed  Google Scholar 

  92. Park YN, Yang CP, Fernandez GJ et al (1998) Neoangiogenesis and sinusoidal “capillarization” in dysplastic nodules of the liver. Am J Surg Pathol 22:656–662

    Article  CAS  PubMed  Google Scholar 

  93. Ueda K, Terada T, Nakanuma Y et al (1992) Vascular supply in adenomatous hyperplasia of the liver and hepatocellular carcinoma: a morphometric study. Hum Pathol 23:619–626

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a Grant-in-Aid for Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor, and Welfare of Japan and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest

No author has any conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nobuyoshi Hiraoka.

About this article

Cite this article

Hiraoka, N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. Int J Clin Oncol 15, 544–551 (2010). https://doi.org/10.1007/s10147-010-0130-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-010-0130-1

Keywords

Navigation