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

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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.

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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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Authors and Affiliations

  1. Functional Biology Department. Instituto Universitario Oncologico del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain

    Leticia Huergo-Zapico, Alejandro López-Soto, Azahara Fernandez-Guizan, Andrea Acebes-Huerta & Juan R. de los Toyos

  2. Hematology Department, Hospital Cabueñes, Gijón, Spain

    Ana P. Gonzalez-Rodriguez, Juan Contesti & Esther Gonzalez

  3. Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain

    Carlos Lopez-Larrea

  4. Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA

    Veronika Groh & Thomas Spies

  5. Functional Biology Department. Instituto Universitario Oncologico del Principado de Asturias (IUOPA), Universidad de Oviedo, 4 ª planta, despacho D02, Julián Clavería sn, 33006, Oviedo, Spain

    Segundo Gonzalez

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  1. Leticia Huergo-Zapico
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  2. Ana P. Gonzalez-Rodriguez
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  11. Thomas Spies
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  12. Segundo Gonzalez
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Correspondence to Segundo Gonzalez.

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Huergo-Zapico, L., Gonzalez-Rodriguez, A.P., Contesti, J. et al. Expression of ERp5 and GRP78 on the membrane of chronic lymphocytic leukemia cells: association with soluble MICA shedding. Cancer Immunol Immunother 61, 1201–1210 (2012). https://doi.org/10.1007/s00262-011-1195-z

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