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Apoptosis and anergy of T cell induced by pancreatic stellate cells-derived galectin-1 in pancreatic cancer

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Tumor Biology

Abstract

Galectin-1, a β-galactoside-binding protein implicated in cancer cell immune privilege, was highly expressed in activated pancreatic stellate cells (PSCs). This study was designed to investigate the relationship between PSC-derived galectin-1 and tumor immunity in pancreatic cancer. Isolated PSCs were identified as normal pancreas cells (hNPSCs) or pancreatic cancer cells (hCaPSCs) by immunohistochemical staining for α-SMA and vimentin, and galectin-1 expression was evaluated by Western blotting and quantitative RT-PCR. Apoptosis, caspase activity, and cytokine production (IL-6, IL-10, TNF-β, and IFN-γ) of T cells co-cultured with PSCs were evaluated, and immunohistochemical staining of galectin-1 was correlated with CD3 and clinicopathological variables in 66 pancreatic cancer and 10 normal pancreatic tissue samples. hCaPSCs exhibited higher galectin-1 expression than did hNPSCs, and hCaPSCs induced higher levels of apoptosis in T cells following co-culture. hCaPSCs activated caspase-9 and caspase-3 in the mitochondrial apoptotic pathway and stimulated secretion of Th2 cytokines (IL-6 and IL-10) but decreased secretion of Th1 cytokines (TNF-β and IFN-γ), compared with hNPSCs. Immunohistochemical staining indicated that galectin-1 and CD3 were more highly expressed in pancreatic cancer tissue. Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage. However, CD3 expression showed the opposite trend and was highest in well-differentiated pancreatic cancer cells and was associated with tumor differentiation and UICC stage. High expression of galectin-1 was associated with short survival, as was low expression of CD3. hCaPSC-derived galectin-1 enhanced apoptosis and anergy of T cells in pancreatic cancer, which contributes to the immune escape of pancreatic cancer cells.

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References

  1. Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467:1109–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  3. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kleeff J, Beckhove P, Esposito I, Herzig S, Huber PE, et al. Pancreatic cancer microenvironment. Int J Cancer. 2007;121:699–705.

    Article  CAS  PubMed  Google Scholar 

  5. Neesse A, Michl P, Frese KK, Feig C, Cook N, et al. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861–8.

    Article  PubMed  Google Scholar 

  6. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330:827–30.

    Article  CAS  PubMed  Google Scholar 

  8. Ganss R, Hanahan D. Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes. Cancer Res. 1998;58:4673–81.

    CAS  PubMed  Google Scholar 

  9. Guturu P, Shah V, Urrutia R. Interplay of tumor microenvironment cell types with parenchymal cells in pancreatic cancer development and therapeutic implications. J Gastrointest Cancer. 2009;40:1–9.

    Article  PubMed  Google Scholar 

  10. Salatino M, Croci DO, Bianco GA, Ilarregui JM, Toscano MA, et al. Galectin-1 as a potential therapeutic target in autoimmune disorders and cancer. Expert Opin Biol Ther. 2008;8:45–57.

    Article  CAS  PubMed  Google Scholar 

  11. Hughes RC. Galectins as modulators of cell adhesion. Biochimie. 2001;83:667–76.

    Article  CAS  PubMed  Google Scholar 

  12. Rabinovich GA. Galectin-1 as a potential cancer target. Br J Cancer. 2005;92:1188–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cimmino F, Schulte JH, Zollo M, Koster J, Versteeg R, et al. Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness. Oncogene. 2009;28:2015–23.

    Article  CAS  PubMed  Google Scholar 

  14. Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, et al. The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2007;104:13134–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tang D, Zhang J, Yuan Z, Gao J, Wang S, et al. Pancreatic satellite cells derived galectin-1 increase the progression and less survival of pancreatic ductal adenocarcinoma. PLoS ONE. 2014;9(3):e90476.

    Article  PubMed  PubMed Central  Google Scholar 

  16. He J, Baum LG. Presentation of galectin-1 by extracellular matrix triggers T cell death. J Biol Chem. 2004;279:4705–12.

    Article  CAS  PubMed  Google Scholar 

  17. Kovacs-Solyom F, Blasko A, Fajka-Boja R, Katona RL, Vegh L, et al. Mechanism of tumor cell-induced T-cell apoptosis mediated by galectin-1. Immunol Lett. 2010;127:108–18.

    Article  CAS  PubMed  Google Scholar 

  18. Motran CC, Molinder KM, Liu SD, Poirier F, Miceli MC. Galectin-1 functions as a Th2 cytokine that selectively induces Th1 apoptosis and promotes Th2 function. Eur J Immunol. 2008;38:3015–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, et al. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; a potential mechanism of tumor-immune privilege. Cancer Cell. 2004;5:241–51.

    Article  CAS  PubMed  Google Scholar 

  20. Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z, et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 2008;68:2085–93.

    Article  CAS  PubMed  Google Scholar 

  21. Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol. 2010;177:2585–96.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Masamune A, Satoh M, Hirabayashi J, Kasai K, Satoh K, et al. Galectin-1 induces chemokine production and proliferation in pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2006;290:G729–736.

    Article  CAS  PubMed  Google Scholar 

  23. Chu GC, Kimmelman AC, Hezel AF, DePinho RA. Stromal biology of pancreatic cancer. J Cell Biochem. 2007;101:887–907.

    Article  CAS  PubMed  Google Scholar 

  24. Ikenaga N, Ohuchida K, Mizumoto K, Cui L, Kayashima T, et al. (2010) CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology 139: 1041-1051, 1051 e1041-1048.

  25. Tang D, Yuan Z, Xue X, Lu Z, Zhang Y, et al. High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int J Cancer. 2012;130:2337–48.

    Article  CAS  PubMed  Google Scholar 

  26. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115:421–32.

    Article  CAS  PubMed  Google Scholar 

  27. Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 2004;64:3215–22.

    Article  CAS  PubMed  Google Scholar 

  28. Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68:918–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Masamune A, Kikuta K, Watanabe T, Satoh K, Satoh A, et al. Pancreatic stellate cells express Toll-like receptors. J Gastroenterol. 2008;43:352–62.

    Article  CAS  PubMed  Google Scholar 

  30. Park HD, Lee Y, Oh YK, Jung JG, Park YW, et al. Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation. Oncogene. 2011;30:201–11.

    Article  CAS  PubMed  Google Scholar 

  31. Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity. 2010;32:790–802.

    Article  CAS  PubMed  Google Scholar 

  32. Epardaud M, Elpek KG, Rubinstein MP, Yonekura AR, Bellemare-Pelletier A, et al. Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res. 2008;68:2972–83.

    Article  CAS  PubMed  Google Scholar 

  33. Plate JM, Harris JE. Immunobiotherapy directed against mutated and aberrantly expressed gene products in pancreas cancer. J Cell Biochem. 2005;94:1069–77.

    Article  CAS  PubMed  Google Scholar 

  34. Perillo NL, Pace KE, Seilhamer JJ, Baum LG. Apoptosis of T cells mediated by galectin-1. Nature. 1995;378:736–9.

    Article  CAS  PubMed  Google Scholar 

  35. Fitzner B, Walzel H, Sparmann G, Emmrich J, Liebe S, et al. Galectin-1 is an inductor of pancreatic stellate cell activation. Cell Signal. 2005;17:1240–7.

    Article  CAS  PubMed  Google Scholar 

  36. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117:1175–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1–50.

    Article  CAS  PubMed  Google Scholar 

  38. Yang RY, Liu FT. Galectins in cell growth and apoptosis. Cell Mol Life Sci. 2003;60:267–76.

    Article  CAS  PubMed  Google Scholar 

  39. Liu FT. Regulatory roles of galectins in the immune response. Int Arch Allergy Immunol. 2005;136:385–400.

    Article  CAS  PubMed  Google Scholar 

  40. Tang D, Wang D, Yuan Z, Xue X, Zhang Y, et al. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer. 2013;132:993–1003.

    Article  CAS  PubMed  Google Scholar 

  41. Blaser C, Kaufmann M, Muller C, Zimmermann C, Wells V, et al. Beta-galactoside-binding protein secreted by activated T cells inhibits antigen-induced proliferation of T cells. Eur J Immunol. 1998;28:2311–9.

    Article  CAS  PubMed  Google Scholar 

  42. Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, et al. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat Immunol. 2007;8:825–34.

    Article  CAS  PubMed  Google Scholar 

  43. Hahn HP, Pang M, He J, Hernandez JD, Yang RY, et al. Galectin-1 induces nuclear translocation of endonuclease G in caspase- and cytochrome c-independent T cell death. Cell Death Differ. 2004;11:1277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ion G, Fajka-Boja R, Kovacs F, Szebeni G, Gombos I, et al. Acid sphingomyelinase mediated release of ceramide is essential to trigger the mitochondrial pathway of apoptosis by galectin-1. Cell Signal. 2006;18:1887–96.

    Article  CAS  PubMed  Google Scholar 

  45. Duner S, Lopatko Lindman J, Ansari D, Gundewar C, Andersson R. Pancreatic cancer: the role of pancreatic stellate cells in tumor progression. Pancreatology. 2011;10:673–81.

    Article  Google Scholar 

  46. Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, et al. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun. 2010;403:380–4.

    Article  CAS  PubMed  Google Scholar 

  47. Berberat PO, Friess H, Wang L, Zhu Z, Bley T, et al. Comparative analysis of galectins in primary tumors and tumor metastasis in human pancreatic cancer. J Histochem Cytochem. 2001;49:539–49.

    Article  CAS  PubMed  Google Scholar 

  48. Li L, Bimmler D, Graf R, Zhou S, Sun Z, et al. PSP/reg inhibits cultured pancreatic stellate cell and regulates MMP/TIMP ratio. Eur J Clin Invest. 2011;41:151–8.

    Article  CAS  PubMed  Google Scholar 

  49. Montiel JL, Monsivais-Urenda A, Figueroa-Vega N, Moctezuma JF, Burgos-Vargas R, et al. Anti-CD43 and anti-galectin-1 autoantibodies in patients with systemic lupus erythematosus. Scand J Rheumatol. 2010;39:50–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank the staff of the Virology Laboratory at the Medical College of YangZhou University for their assistance. This work was supported by grants from the Postdoctoral Science Foundation of China (No. 2013M530243), the Social Development of Science and Technology Research Projects of Yangzhou City (No. 2012123), the Jiangsu Province Natural Science Foundation of China (BK20140495), and the Six Big Talent Peak Projects of Jiangsu Province (2014-WSW-078).

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Correspondence to Daorong Wang or Kuirong Jiang.

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Dong Tang and Jun Gao contributed equally to this work.

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Tang, D., Gao, J., Wang, S. et al. Apoptosis and anergy of T cell induced by pancreatic stellate cells-derived galectin-1 in pancreatic cancer. Tumor Biol. 36, 5617–5626 (2015). https://doi.org/10.1007/s13277-015-3233-5

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  • DOI: https://doi.org/10.1007/s13277-015-3233-5

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