Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing gammadelta T cell cytotoxicity.
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 gammadelta 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 gammadelta 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 gammadelta T and NK cells was investigated by cytotoxicity assays. Subsequently, the effect of IFN-alpha 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 gammadelta 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-alpha 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 gammadelta T cells and NK cells. IFN-alpha, which is used in adjuvant treatment of pancreatic carcinoma, might partly act via up-regulation of MIC without induction of sMIC release.
Märten
Angela
A
Department of Surgery, University of Heidelberg, 69120 Heidelberg, Germany. angela.maerten@med.uni-heidelberg.de
von Lilienfeld-Toal
Marie
M
Büchler
Markus W
MW
Schmidt
Jan
J
D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000097:blood* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; C099187:MHC class I-related chain A; D016692:Receptors, Antigen, T-Cell, gamma-delta