Top

Published in:

01-01-2012 | Original Article

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

Authors: Matthias M. Gaida, Thilo Welsch, Esther Herpel, Darjus F. Tschaharganeh, Lars Fischer, Peter Schirmacher, G. Maria Hänsch, Frank Bergmann

Published in: Virchows Archiv | Issue 1/2012

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.

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

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

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

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

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

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):754–759PubMedCrossRef

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):630–636PubMedCrossRef

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):10–16PubMedCrossRef

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):1419–1428PubMed

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):297–308PubMed

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):216–223PubMedCrossRef

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):209–217PubMedCrossRef

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):3530–3535PubMed

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):301–311PubMedCrossRef

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):222–231PubMedCrossRef

16.

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

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):138–142PubMedCrossRef

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):377–378PubMed

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):3930–3935PubMed

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):4163–4170PubMedCrossRef

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):1231–1237PubMedCrossRef

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):47–54PubMed

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):436–442PubMedCrossRef

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):80–85PubMedCrossRef

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):127–135PubMedCrossRef

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):521–530PubMedCrossRef

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

28.

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

29.

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

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

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):395–401PubMedCrossRef

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):171–181PubMedCrossRef

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):534–544PubMedCrossRef

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):1417–1427PubMed

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):3591–3596PubMedCrossRef

36.

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

37.

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

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):6800–6807PubMedCrossRef

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):91–102PubMedCrossRef

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):350–358PubMedCrossRef

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):3073–3081PubMed

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):93–98PubMedCrossRef

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):10079–10087PubMedCrossRef

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):236–247PubMedCrossRef

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):127–133PubMedCrossRef

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):67–73PubMedCrossRef

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):461–466PubMed

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):4128–4135PubMed

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):507–518PubMedCrossRef

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):6047–6055PubMed

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–e31PubMedCrossRef

52.

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

53.

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

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):768–778PubMedCrossRef

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):1303–1310PubMedCrossRef

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

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):1195–1204PubMed

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):4968–4977PubMedCrossRef

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):84–92PubMed

60.

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

Title: MHC class II expression in pancreatic tumors: a link to intratumoral inflammation
Authors: Matthias M. Gaida
Thilo Welsch
Esther Herpel
Darjus F. Tschaharganeh
Lars Fischer
Peter Schirmacher
G. Maria Hänsch
Frank Bergmann
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 1/2012
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-011-1175-x

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Frozen section analysis of sentinel lymph nodes in patients with breast cancer does not impair the probability to detect lymph node metastases

Personalized cancer medicine and the future of pathology

Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED)

Eosinophilic myenteric ganglionitis as a cause of chronic intestinal pseudo-obstruction

CD99 is expressed in chordoid glioma and suggests ependymal origin

Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants