Skip to main content
SpringerLink
Log in

Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The aim of this paper was to determine the clinical significance of the MHC class I chain-related molecule A(MICA) and NKG2D receptor on NK cells in pancreatic cancer. We compared MICA expression in malignant (n = 103), inflammatory (n = 28), and normal (n = 17) pancreatic tissues using immunohistochemistry and assessed serum levels of soluble MICA (sMICA) and NKG2D expression on NK cells in patients with pancreatic cancer (n = 103), in patients with chronic pancreatitis (n = 28), and in healthy volunteers (n = 43). Expression of MICA was detected in 89.3% of pancreatic cancer tissues, whereas fewer were expressed in inflammatory and normal pancreatic tissues. The levels of sMICA were frequently elevated in patients with advanced pancreatic cancer. The elevation of sMICA was associated with down-regulated NKG2D expression and impaired activity of NK cells. The successful tumor resection significantly decreased serum levels of sMICA and increased the NKG2D expression; there was an inverse correlation between change in sMICA levels and that in NKG2D expression. MICA expression, preoperative sMICA levels and NKG2D intensity were found to be independent prognostic factors in resected pancreatic cancer. This study supports the clinical significance of release of MICA for the malignant progression of pancreatic cancer. The successful tumor resection for pancreatic cancer may have a beneficial effect on NKG2D-mediated antitumor immunity. Our results also suggest sMICA and NKG2D expression on NK cells may be useful to identify risk patients at time point of diagnosis.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jemal A, et al. Cancer statistics 2007. CA Cancer J Clin. 2007;57(1):43–66.

    Article  PubMed  Google Scholar 

  2. Levi F, Lucchini F, Negri E, La Vecchia C. Pancreatic cancer mortality in Europe: the leveling of an epidemic. Pancreas. 2003;27(2):139–42.

    Article  PubMed  Google Scholar 

  3. Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM. In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA. 2000;97(6):2731–6.

    Article  PubMed  CAS  Google Scholar 

  4. Pross HF, Lotzova E. Role of natural killer cells in cancer. Nat Immunol. 1993;12(4–5):279–92.

    CAS  Google Scholar 

  5. Aparicio-Pagés MN, Verspaget HW, Peña AS, Lamers CB. Natural killer cell activity in patients with adenocarcinoma in the upper gastrointestinal tract. J Clin Lab Immunol. 1991;35(1):27–32.

    PubMed  Google Scholar 

  6. Bauer S, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress -inducible MICA. Science. 1999;285(5428):727–9.

    Article  PubMed  CAS  Google Scholar 

  7. Groh V, et al. Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci USA. 1999;96(12):6879–84.

    Article  PubMed  CAS  Google Scholar 

  8. Vetter CS, et al. Expression of stress-induced MHC class I related chain molecules on human melanoma. J Invest Dermatol. 2002;118(4):600–5.

    Article  PubMed  CAS  Google Scholar 

  9. Jinushi M, et al. Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer. 2003;104(3):354–61.

    Article  PubMed  CAS  Google Scholar 

  10. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3(10):781–90.

    Article  PubMed  CAS  Google Scholar 

  11. Eisele G, et al. TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain. 2006;129(Pt 9):2416–25.

    Article  PubMed  Google Scholar 

  12. Watson NF, et al. Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int J Cancer. 2006;18(6):1445–52.

    Article  Google Scholar 

  13. Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol. 2002;169(8):4098–102.

    PubMed  CAS  Google Scholar 

  14. Holdenrieder S, et al. Soluble MICA in malignant diseases. Int J Cancer. 2006;118(3):684–7.

    Article  PubMed  CAS  Google Scholar 

  15. Rebmann V, et al. Soluble MICA as an independent prognostic factor for the overall survival and progression-free survival of multiple myeloma patients. Clin Immunol. 2007;123(1):114–20.

    Article  PubMed  CAS  Google Scholar 

  16. Vetter CS, Lieb W, Brocker E-B, Becker JC. Loss of non-classical MHC molecules MIC-A/B expression during progression of uveal melanoma. Br J Cancer. 2004;91(8):1495–9.

    PubMed  CAS  Google Scholar 

  17. Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002;419(6908):734–8.

    Article  PubMed  CAS  Google Scholar 

  18. Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature. 2001;413(6852):165–71.

    Article  PubMed  CAS  Google Scholar 

  19. Li K, et al. Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: high expression of ULBP2 is an indicator of poor prognosis. Cancer Immunol Immunother. 2009;58(5):641–52.

    Article  PubMed  CAS  Google Scholar 

  20. Ohashi M, et al. Adenovirus-mediated interferon gene transfer induces regional direct cytotoxicity and possible systemic immunity against pancreatic cancer. Br J Cancer. 2005;93(4):441–9.

    Article  PubMed  CAS  Google Scholar 

  21. Boissel N, et al. BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J Immunol. 2006;176(8):5108–16.

    PubMed  CAS  Google Scholar 

  22. Routes JM, et al. Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection. J Exp Med. 2005;202(11):1477–82.

    Article  PubMed  CAS  Google Scholar 

  23. Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature. 2005;436(7054):1186–90.

    Article  PubMed  CAS  Google Scholar 

  24. Märten A, von Lilienfeld-Toal M, Büchler MW, Schmidt J. Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing gammadelta T cell cytotoxicity. Int J Cancer. 2006;119(10):2359–65.

    Article  PubMed  Google Scholar 

  25. Doubrovina ES, et al. Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol. 2003;171(12):6891–9.

    PubMed  CAS  Google Scholar 

  26. Wu JD, et al. Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest. 2004;114(4):560–8.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gerneral Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, 410008, Changsha, Hunan Province, People’s Republic of China

    Xiaohui Duan, Xiong Chen, Yebin Lu, Qi Zhang, Kejing Zhang, Yongjun Hu, Jie Zeng & Weijia Sun

  2. Department of Gastroenterology, Xiangya Hospital, Central South University, 87 Xiangya Road, 410008, Changsha, Hunan Province, People’s Republic of China

    Langmei Deng

Authors
  1. Xiaohui Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Langmei Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yebin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kejing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongjun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jie Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Weijia Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weijia Sun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Duan, X., Deng, L., Chen, X. et al. Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer. Med Oncol 28, 466–474 (2011). https://doi.org/10.1007/s12032-010-9480-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-010-9480-9

Keywords

Search

Navigation