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MHC class II expression in pancreatic tumors: a link to intratumoral inflammation

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Abstract

Major histocompatibility complex class II antigens (MHC class II) are constitutively expressed by professional antigen presenting cells and present antigenic peptides to specific CD4+ T lymphocytes. MHC class II expression, however, can also be induced on epithelial cells and in a variety of solid tumors. We tested MHC class II expression on tissue samples derived from patients with pancreatic ductal adenocarcinoma (PDAC) and pancreatic endocrine tumors (PET). Immunohistochemistry revealed MHC class II expression in 86 of 112 (76.8%) PDAC samples and in 30 of 43 (70.0%) PET samples. In PDAC and PET, MHC class II expression correlated significantly with severity and activity of intratumoral inflammation, as well as with the infiltration of CD4+ T lymphocytes. High MHC class II expression significantly correlated with a better histological grade of differentiation in PDAC. In vitro MHC class II expression could be induced on PDAC tumor cell lines by interferon-γ. These cells were then able to present the staphylococci enterotoxin B superantigen to T lymphocytes, which resulted in T cell proliferation. Our findings suggest that MHC class II expression on pancreatic tumor cells is induced by the intratumoral inflammatory reaction in pancreatic tumors.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249

    Article  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  PubMed  CAS  Google Scholar 

  3. Kleeff J, Beckhove P, Esposito I, Herzig S, Huber PE, Lohr JM, Friess H (2007) Pancreatic cancer microenvironment. Int J Cancer 121(4):699–705

    Article  PubMed  CAS  Google Scholar 

  4. Welsch T, Kleeff J, Friess H (2007) Molecular pathogenesis of pancreatic cancer: advances and challenges. Curr Mol Med 7(5):504–521

    Article  PubMed  CAS  Google Scholar 

  5. Greer JB, Whitcomb DC (2009) Inflammation and pancreatic cancer: an evidence-based review. Curr Opin Pharmacol 9(4):411–418

    Article  PubMed  CAS  Google Scholar 

  6. Tingstedt B, Johansson P, Andersson B, Andersson R (2007) Predictive factors in pancreatic ductal adenocarcinoma: role of the inflammatory response. Scand J Gastroenterol 42(6):754–759

    Article  PubMed  CAS  Google Scholar 

  7. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, Bevilacqua G, Campani D (2004) Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 57(6):630–636

    Article  PubMed  CAS  Google Scholar 

  8. Bolignano D, Donato V, Lacquaniti A, Fazio MR, Bono C, Coppolino G, Buemi M (2010) Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: a new protein enters the scene. Cancer Lett 288(1):10–16

    Article  PubMed  CAS  Google Scholar 

  9. Schmitz-Winnenthal FH, Escobedo LV, Beckhove P, Schirrmacher V, Bucur M, Ziouta Y, Volk C, Schmied B, Koch M, Antolovic D, Weitz J, Buchler MW, Z'Graggen K (2006) Specific immune recognition of pancreatic carcinoma by patient-derived CD4 and CD8 T cells and its improvement by interferon-gamma. Int J Oncol 28(6):1419–1428

    PubMed  CAS  Google Scholar 

  10. Wente MN, Gaida MM, Mayer C, Michalski CW, Haag N, Giese T, Felix K, Bergmann F, Giese NA, Friess H (2008) Expression and potential function of the CXC chemokine CXCL16 in pancreatic ductal adenocarcinoma. Int J Oncol 33(2):297–308

    PubMed  CAS  Google Scholar 

  11. Gaida MM, Gunther F, Wagner C, Friess H, Giese NA, Schmidt J, Hansch GM, Wente MN (2008) Expression of the CXCR6 on polymorphonuclear neutrophils in pancreatic carcinoma and in acute, localized bacterial infections. Clin Exp Immunol 154(2):216–223

    Article  PubMed  CAS  Google Scholar 

  12. Wente MN, Mayer C, Gaida MM, Michalski CW, Giese T, Bergmann F, Giese NA, Buchler MW, Friess H (2008) CXCL14 expression and potential function in pancreatic cancer. Cancer Lett 259(2):209–217

    Article  PubMed  CAS  Google Scholar 

  13. Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N, Imamura M (2000) Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res 6(9):3530–3535

    PubMed  CAS  Google Scholar 

  14. Scupoli MT, Sartoris S, Tosi G, Ennas MG, Nicolis M, Cestari T, Zamboni G, Martignoni G, Lemoine NR, Scarpa A, Accolla RS (1996) Expression of MHC class I and class II antigens in pancreatic adenocarcinomas. Tissue Antigens 48(4 Pt 1):301–311

    Article  PubMed  CAS  Google Scholar 

  15. Berghuis D, de Hooge AS, Santos SJ, Horst D, Wiertz EJ, van Eggermond MC, van den Elsen PJ, Taminiau AH, Ottaviano L, Schaefer KL, Dirksen U, Hooijberg E, Mulder A, Melief CJ, Egeler RM, Schilham MW, Jordanova ES, Hogendoorn PC, Lankester AC (2009) Reduced human leukocyte antigen expression in advanced-stage Ewing sarcoma: implications for immune recognition. J Pathol 218(2):222–231

    Article  PubMed  CAS  Google Scholar 

  16. Townsend A, Bodmer H (1989) Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol 7:601–624

    Article  PubMed  CAS  Google Scholar 

  17. Albanesi C, Cavani A, Girolomoni G (1998) Interferon-gamma-stimulated human keratinocytes express the genes necessary for the production of peptide-loaded MHC class II molecules. J Invest Dermatol 110(2):138–142

    Article  PubMed  CAS  Google Scholar 

  18. Fais S, Capobianchi MR, Marcheggiano A, Iannoni C, Pallone F (1992) MHC class II antigens on the epithelial cells of the human gastrointestinal tract. Gastroenterology 102(1):377–378

    PubMed  CAS  Google Scholar 

  19. Ruiter DJ, Bergman W, Welvaart K, Scheffer E, van Vloten WA, Russo C, Ferrone S (1984) Immunohistochemical analysis of malignant melanomas and nevocellular nevi with monoclonal antibodies to distinct monomorphic determinants of HLA antigens. Cancer Res 44(9):3930–3935

    PubMed  CAS  Google Scholar 

  20. Dengjel J, Nastke MD, Gouttefangeas C, Gitsioudis G, Schoor O, Altenberend F, Muller M, Kramer B, Missiou A, Sauter M, Hennenlotter J, Wernet D, Stenzl A, Rammensee HG, Klingel K, Stevanovic S (2006) Unexpected abundance of HLA class II presented peptides in primary renal cell carcinomas. Clin Cancer Res 12(14 Pt 1):4163–4170

    Article  PubMed  CAS  Google Scholar 

  21. Walsh MD, Dent OF, Young JP, Wright CM, Barker MA, Leggett BA, Bokey L, Chapuis PH, Jass JR, Macdonald GA (2009) HLA-DR expression is associated with better prognosis in sporadic Australian clinicopathological Stage C colorectal cancers. Int J Cancer 125(5):1231–1237

    Article  PubMed  CAS  Google Scholar 

  22. Concha A, Esteban F, Cabrera T, Ruiz-Cabello F, Garrido F (1991) Tumor aggressiveness and MHC class I and II antigens in laryngeal and breast cancer. Semin Cancer Biol 2(1):47–54

    PubMed  CAS  Google Scholar 

  23. Esteban F, Concha A, Huelin C, Perez-Ayala M, Pedrinaci S, Ruiz-Cabello F, Garrido F (1989) Histocompatibility antigens in primary and metastatic squamous cell carcinoma of the larynx. Int J Cancer 43(3):436–442

    Article  PubMed  CAS  Google Scholar 

  24. Andersen SN, Rognum TO, Lund E, Meling GI, Hauge S (1993) Strong HLA-DR expression in large bowel carcinomas is associated with good prognosis. Br J Cancer 68(1):80–85

    Article  PubMed  CAS  Google Scholar 

  25. Pandha H, Rigg A, John J, Lemoine N (2007) Loss of expression of antigen-presenting molecules in human pancreatic cancer and pancreatic cancer cell lines. Clin Exp Immunol 148(1):127–135

    Article  PubMed  CAS  Google Scholar 

  26. Radsak M, Iking-Konert C, Stegmaier S, Andrassy K, Hansch GM (2000) Polymorphonuclear neutrophils as accessory cells for T-cell activation: major histocompatibility complex class II restricted antigen-dependent induction of T-cell proliferation. Immunology 101(4):521–530

    Article  PubMed  CAS  Google Scholar 

  27. Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) (2010) World Health Organisation classification of tumours. Pathology and genetics of tumours of the digestive system. Ductal adenocarcinoma of the pancreas. IARC Press, Lyon

    Google Scholar 

  28. Sobin LH, Gospodarowicz MK, Wittekind C (2009) TNM classification of malignant tumours, 7th edition. Wiley, Oxford

    Google Scholar 

  29. Heitz PU, Komminoth P, Perren A (2004) Tumours of endocrine organs: pathology and genetics World Health Organisation classification of tumors. IARC press, Lyon

    Google Scholar 

  30. Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) World Health Organisation classification of tumours. Pathology and genetics of tumours of the digestive system. Neuroendocrine neoplasms of the pancreas. IARC press, Lyon

    Google Scholar 

  31. Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Korner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449(4):395–401

    Article  PubMed  CAS  Google Scholar 

  32. Bergmann F, Breinig M, Hopfner M, Rieker RJ, Fischer L, Kohler C, Esposito I, Kleeff J, Herpel E, Ehemann V, Friess H, Schirmacher P, Kern MA (2009) Expression pattern and functional relevance of epidermal growth factor receptor and cyclooxygenase-2: novel chemotherapeutic targets in pancreatic endocrine tumors? Am J Gastroenterol 104(1):171–181

    Article  PubMed  CAS  Google Scholar 

  33. Ceyhan GO, Bergmann F, Kadihasanoglu M, Erkan M, Park W, Hinz U, Giese T, Muller MW, Buchler MW, Giese NA, Friess H (2007) The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut 56(4):534–544

    Article  PubMed  CAS  Google Scholar 

  34. Bijen CB, Bantema-Joppe EJ, de Jong RA, Leffers N, Mourits MJ, Eggink HF, van der Zee AG, Hollema H, de Bock GH, Nijman HW (2010) The prognostic role of classical and nonclassical MHC class I expression in endometrial cancer. Int J Cancer 126(6):1417–1427

    PubMed  CAS  Google Scholar 

  35. Rolland P, Deen S, Scott I, Durrant L, Spendlove I (2007) Human leukocyte antigen class I antigen expression is an independent prognostic factor in ovarian cancer. Clin Cancer Res 13(12):3591–3596

    Article  PubMed  CAS  Google Scholar 

  36. Itano AA, Jenkins MK (2003) Antigen presentation to naive CD4 T cells in the lymph node. Nat Immunol 4(8):733–739

    Article  PubMed  CAS  Google Scholar 

  37. Rocha N, Neefjes J (2008) MHC class II molecules on the move for successful antigen presentation. EMBO J 27(1):1–5

    Article  PubMed  CAS  Google Scholar 

  38. Radfar S, Wang Y, Khong HT (2009) Activated CD4+ T cells dramatically enhance chemotherapeutic tumor responses in vitro and in vivo. J Immunol 183(10):6800–6807

    Article  PubMed  CAS  Google Scholar 

  39. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM (2009) CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16(2):91–102

    Article  PubMed  CAS  Google Scholar 

  40. Han DC, Huang GT, Lin LM, Warner NA, Gim JS, Jewett A (2003) Expression of MHC Class II, CD70, CD80, CD86 and pro-inflammatory cytokines is differentially regulated in oral epithelial cells following bacterial challenge. Oral Microbiol Immunol 18(6):350–358

    Article  PubMed  CAS  Google Scholar 

  41. Giacomini P, Tecce R, Gambari R, Sacchi A, Fisher PB, Natali PG (1988) Recombinant human IFN-gamma, but not IFN-alpha or IFN-beta, enhances MHC- and non-MHC-encoded glycoproteins by a protein synthesis-dependent mechanism. J Immunol 140(9):3073–3081

    PubMed  CAS  Google Scholar 

  42. Tang KF, Chan SH, Loh KS, Chong SM, Wang D, Yeoh KH, Hu H (1999) Increased production of interferon-gamma by tumour infiltrating T lymphocytes in nasopharyngeal carcinoma: indicative of an activated status. Cancer Lett 140(1–2):93–98

    Article  PubMed  CAS  Google Scholar 

  43. Schmitz-Winnenthal FH, Volk C, Z'Graggen K, Galindo L, Nummer D, Ziouta Y, Bucur M, Weitz J, Schirrmacher V, Buchler MW, Beckhove P (2005) High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 65(21):10079–10087

    Article  PubMed  CAS  Google Scholar 

  44. Monti P, Marchesi F, Reni M, Mercalli A, Sordi V, Zerbi A, Balzano G, Di Carlo V, Allavena P, Piemonti L (2004) A comprehensive in vitro characterization of pancreatic ductal carcinoma cell line biological behavior and its correlation with the structural and genetic profile. Virchows Arch 445(3):236–247

    Article  PubMed  CAS  Google Scholar 

  45. Nickoloff BJ, Mitra RS, Green J, Shimizu Y, Thompson C, Turka LA (1993) Activated keratinocytes present bacterial-derived superantigens to T lymphocytes: relevance to psoriasis. J Dermatol Sci 6(2):127–133

    Article  PubMed  CAS  Google Scholar 

  46. Schulz H, Karau A, Filsinger S, Schoels M, Kabelitz D, Richter R, Hansch GM (1998) Tubular epithelial cells as accessory cells for superantigen-induced T cell activation. Exp Nephrol 6(1):67–73

    Article  PubMed  CAS  Google Scholar 

  47. Kraft M, Filsinger S, Kramer KL, Kabelitz D, Hansch GM, Schoels M (1995) Synovial fibroblasts as accessory cells for staphylococcal enterotoxin-mediated T-cell activation. Immunology 85(3):461–466

    PubMed  CAS  Google Scholar 

  48. Fanger NA, Liu C, Guyre PM, Wardwell K, O'Neil J, Guo TL, Christian TP, Mudzinski SP, Gosselin EJ (1997) Activation of human T cells by major histocompatability complex class II expressing neutrophils: proliferation in the presence of superantigen, but not tetanus toxoid. Blood 89(11):4128–4135

    PubMed  CAS  Google Scholar 

  49. Muller-Hermelink N, Braumuller H, Pichler B, Wieder T, Mailhammer R, Schaak K, Ghoreschi K, Yazdi A, Haubner R, Sander CA, Mocikat R, Schwaiger M, Forster I, Huss R, Weber WA, Kneilling M, Rocken M (2008) TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13(6):507–518

    Article  PubMed  Google Scholar 

  50. Marzo AL, Kinnear BF, Lake RA, Frelinger JJ, Collins EJ, Robinson BW, Scott B (2000) Tumor-specific CD4+ T cells have a major "post-licensing" role in CTL mediated anti-tumor immunity. J Immunol 165(11):6047–6055

    PubMed  CAS  Google Scholar 

  51. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, Kato K, Kurokawa T, Suzuoki M, Nakakubo Y, Hiraoka K, Itoh T, Morikawa T, Okushiba S, Kondo S, Katoh H (2004) CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 28(1):e26–e31

    Article  PubMed  Google Scholar 

  52. Lindner R, Unanue ER (1996) Distinct antigen MHC class II complexes generated by separate processing pathways. EMBO J 15(24):6910–6920

    PubMed  CAS  Google Scholar 

  53. Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363(9414):1049–1057

    Article  PubMed  CAS  Google Scholar 

  54. Strieter RM, Burdick MD, Mestas J, Gomperts B, Keane MP, Belperio JA (2006) Cancer CXC chemokine networks and tumour angiogenesis. Eur J Cancer 42(6):768–778

    Article  PubMed  CAS  Google Scholar 

  55. Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77(7):1303–1310

    Article  PubMed  CAS  Google Scholar 

  56. von Bernstorff W, Voss M, Freichel S, Schmid A, Vogel I, Johnk C, Henne-Bruns D, Kremer B, Kalthoff H (2001) Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 7(3 Suppl):925s–932s

    Google Scholar 

  57. Ye X, Kralli A, Ge R, Ricciardi RP, Knowles BB (1994) Down-regulation of MHC class I antigen in insulinoma cells controlled by the R1 element of the H-2 enhancer. Oncogene 9(4):1195–1204

    PubMed  CAS  Google Scholar 

  58. Lotem M, Machlenkin A, Hamburger T, Nissan A, Kadouri L, Frankenburg S, Gimmon Z, Elias O, David IB, Kuznetz A, Shiloni E, Peretz T (2009) Autologous melanoma vaccine induces antitumor and self-reactive immune responses that affect patient survival and depend on MHC class II expression on vaccine cells. Clin Cancer Res 15(15):4968–4977

    Article  PubMed  CAS  Google Scholar 

  59. Propper DJ, Chao D, Braybrooke JP, Bahl P, Thavasu P, Balkwill F, Turley H, Dobbs N, Gatter K, Talbot DC, Harris AL, Ganesan TS (2003) Low-dose IFN-gamma induces tumor MHC expression in metastatic malignant melanoma. Clin Cancer Res 9(1):84–92

    PubMed  CAS  Google Scholar 

  60. Schwartz RH (1996) Models of T cell anergy: is there a common molecular mechanism? J Exp Med 184(1):1–8

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Prof. Dr. Ulrich Abel, Department of Medical Biometry, University of Heidelberg for the professional evaluation of the biostatistics. We thank Mrs. Birgit Prior, Institute for Immunology, University of Heidelberg and Mrs. Sarah Messnard, Institute of Pathology, University of Heidelberg for their excellent technical support.

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Correspondence to Frank Bergmann.

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Gaida, M.M., Welsch, T., Herpel, E. et al. MHC class II expression in pancreatic tumors: a link to intratumoral inflammation. Virchows Arch 460, 47–60 (2012). https://doi.org/10.1007/s00428-011-1175-x

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  • DOI: https://doi.org/10.1007/s00428-011-1175-x

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