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Cancer Immunology, Immunotherapy

, Volume 61, Issue 8, pp 1201–1210 | Cite as

Expression of ERp5 and GRP78 on the membrane of chronic lymphocytic leukemia cells: association with soluble MICA shedding

  • Leticia Huergo-Zapico
  • Ana P. Gonzalez-Rodriguez
  • Juan Contesti
  • Esther Gonzalez
  • Alejandro López-Soto
  • Azahara Fernandez-Guizan
  • Andrea Acebes-Huerta
  • Juan R. de los Toyos
  • Carlos Lopez-Larrea
  • Veronika Groh
  • Thomas Spies
  • Segundo GonzalezEmail author
Original Article

Abstract

MICA is a ligand of the activating receptor NKG2D, expressed by NK and T cells. MICA expression is induced in cancer cells favoring their elimination by the immune system; however, many advanced tumors shed soluble MICA (sMICA), which impairs NKG2D-mediated cytotoxicity. ERp5 and GRP78 are endoplasmic reticulum-resident proteins that are translocated to the surface of epithelial tumor cells where they interact with MICA and are involved in sMICA shedding. In this study, we analyze the role of ERp5 and GRP78 in sMICA shedding in chronic lymphocytic leukemia (CLL). Immunofluorescence and flow cytometry analyses showed that ERp5 and GRP78 were significantly expressed on the surface of B cells and leukemia cells, but they were not expressed on T cells. The expression of ERp5 and GRP78 was significantly higher in leukemia cells than in B cells from controls. ERp5 and GRP78 co-localized with MICA on the surface of leukemia cells and the levels of expression of ERp5 and GRP78 correlated with the level of expression of membrane-bound MICA in CLL patients. Associated with higher expression of membrane-bound ERp5 and GRP78, serum sMICA levels were approximately threefold higher in patients than in controls. Elevated sMICA levels in CLL patients were associated with the down-modulation of NKG2D surface expression on CD8 T cells. Finally, pharmacological inhibition of B cell lines and stimulated leukemia cells showed that ERp5 activity is involved in sMICA shedding in CLL. In conclusion, these results uncover a molecular mechanism which regulates MICA protein shedding and immune evasion in CLL.

Keywords

Chronic lymphocytic leukemia NKG2D MICA ERp5 GRP78 NK cells 

Notes

Acknowledgments

This work was supported by the Spanish grants of Fondo de Investigaciones Sanitarias (Institute Carlos III) PS09/00420 and FIS PI08/0566. ALS holds a predoctoral fellowship from FICYT of Asturias (BP06-99).

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Leticia Huergo-Zapico
    • 1
  • Ana P. Gonzalez-Rodriguez
    • 2
  • Juan Contesti
    • 2
  • Esther Gonzalez
    • 2
  • Alejandro López-Soto
    • 1
  • Azahara Fernandez-Guizan
    • 1
  • Andrea Acebes-Huerta
    • 1
  • Juan R. de los Toyos
    • 1
  • Carlos Lopez-Larrea
    • 3
  • Veronika Groh
    • 4
  • Thomas Spies
    • 4
  • Segundo Gonzalez
    • 5
    Email author
  1. 1.Functional Biology Department. Instituto Universitario Oncologico del Principado de Asturias (IUOPA)Universidad de OviedoOviedoSpain
  2. 2.Hematology DepartmentHospital CabueñesGijónSpain
  3. 3.Department of ImmunologyHospital Universitario Central de AsturiasOviedoSpain
  4. 4.Fred Hutchinson Cancer Research CenterClinical Research DivisionSeattleUSA
  5. 5.Functional Biology Department. Instituto Universitario Oncologico del Principado de Asturias (IUOPA)Universidad de OviedoOviedoSpain

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