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

• Published in: Cancer Immunology, Immunotherapy Vol. 61; no. 8; pp. 1201 - 1210
• Main Authors: Huergo-Zapico, Leticia, Gonzalez-Rodriguez, Ana P., Contesti, Juan, Gonzalez, Esther, López-Soto, Alejandro, Fernandez-Guizan, Azahara, Acebes-Huerta, Andrea, de los Toyos, Juan R., Lopez-Larrea, Carlos, Groh, Veronika, Spies, Thomas, Gonzalez, Segundo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.08.2012; Springer; Springer Nature B.V
• Subjects: Aged; Antineoplastic agents; Biological and medical sciences; Cancer; Cancer Research; CD8 antigen; Cells; Chronic lymphatic leukemia; Cytotoxicity; Endoplasmic reticulum; Endoplasmic Reticulum Chaperone BiP; Enzyme-Linked Immunosorbent Assay; Enzymes; Female; Flow Cytometry; Fluorescent Antibody Technique; Hematologic and hematopoietic diseases; Histocompatibility Antigens Class I - metabolism; Humans; Immune system; Immunofluorescence; Immunology; Immunotherapy; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Ligands; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Male; Medical prognosis; Medical research; Medical sciences; Medicine; Medicine & Public Health; MICA protein; Microscopy, Confocal; Molecular modelling; Multiple myeloma; Oncology; Original; Original Article; Patients; Pharmacology. Drug treatments; Polyclonal antibodies; Protein Disulfide-Isomerases - biosynthesis; Proteins; Receptors, Neuropeptide - biosynthesis; Tumor cells; Tumor Escape - physiology; Tumors; Spain; GRP78; Chronic lymphocytic leukemia; NKG2D; ERp5; NK cells; MICA; NKG2D receptor; Malignant hemopathy; Soluble form; Gene expression; In vitro; Natural killer cell; Treatment; Lymphoproliferative syndrome; Immunotherapy; Cancer
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-011-1195-z

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.