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Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing γδ T cell cytotoxicity
Author(s) -
Märten Angela,
von LilienfeldToal Marie,
Büchler Markus W.,
Schmidt Jan
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22186
Subject(s) - cytotoxicity , nkg2d , cancer research , cytotoxic t cell , immune system , biology , immunology , pancreatic cancer , cancer , in vitro , biochemistry , genetics
Intestinal cells express MHC related molecules termed MICA/MICB, which are up‐regulated under stress and in many gastrointestinal tumors. These molecules can be recognized by the immunoreceptor NKG2D, which is present on NK and γδ T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells. The immediate effect of soluble MIC (sMIC) on cellular cytotoxicity of γδ T cells is yet not investigated. We determined sMIC levels in sera of patients with pancreatic carcinoma and the expression of MIC on the surface of tumor cells by FACS. The effect of sMIC content in patient serum on cellular cytotoxicity of γδ T and NK cells was investigated by cytotoxicity assays. Subsequently, the effect of IFN‐α treatment on MIC expression, release and cellular cytotoxicity was investigated. Pancreatic carcinoma cells express MIC, and patient sera contain elevated sMIC levels that correlate with tumor stage and differentiation. Furthermore, cellular cytotoxicity of γδ T cells and NK cells against pancreatic carcinoma is impaired by sMIC in patient sera which is prevented by sMIC neutralization. Incubation of pancreatic cancer cells with IFN‐α increases MIC expression without induction of sMIC resulting in enhanced lysis of tumor cells. Our results demonstrate that sMIC impairs NKG2D‐mediated immunity against pancreatic carcinoma by directly diminishing cytotoxicity of γδ T cells and NK cells. IFN‐α, which is used in adjuvant treatment of pancreatic carcinoma, might partly act via up‐regulation of MIC without induction of sMIC release. © 2006 Wiley‐Liss, Inc.