title: Identification and functional analysis of ligands for natural killer cell activating receptors in colon carcinoma.
abstract: Natural killer (NK) cells play important roles in the immune defense against tumor cells.  The function of NK cells is determined by a balance between activating and inhibitory signals.  DNAX accessory molecule-1 (DNAM-1) and NK group 2 member D (NKG2D) are major NK cell activating receptors, which transduce activating signals after binding their ligands CD155, CD112 and major histocompatibility complex class I-related chains A and B (MICA/B).  However, the expression and functions of these ligands in colon carcinoma are still elusive.  Here, we show the higher expression of CD155, CD112 and MICA/B in colon carcinoma tissues, although no correlations between the ligands expression and patient clinicopathological parameters were found.  The subsequent cytotoxicity assay indicated that NK cells effectively kill colon carcinoma cells.  Functional blocking of these ligands and/or receptors with antibodies led to significant inhibition of NK cell cytotoxicity.  Importantly, expression of DNAM-1 and NKG2D was reduced in NK cells of colon cancer patients, and this reduction could directly suppress the activation of NK cells.  Moreover, colon cancer patients have higher serum concentrations of sCD155 and sMICA/B (soluble ligands, secreted or shed from cells) than those in healthy donors (sCD155, 127.82 ± 44.12 vs. 63.67 ± 22.30 ng/ml; sMICA, 331.51 ± 65.23 vs. 246.74 ± 20.76 pg/ml; and sMICB, 349.42 ± 81.69 vs. 52.61 ± 17.56 pg/ml).  The up-regulation of these soluble ligands may down-regulate DNAM-1 and NKG2D on NK cells, ultimately leading to the inhibition of NK cytotoxicity.  Colon cancer might be a promising target for NK cell-based adoptive immunotherapy.
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, P.R. China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.forename: Liang
authors.initials: L
authors.lastname: He
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Ji
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Guanglong
authors.initials: G
authors.lastname: Dong
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D002277:Carcinoma / Q000276:immunology* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell / Q000378:metabolism*; D011991:Receptors, Virus / Q000097:blood / Q000276:immunology; D018709:Statistics, Nonparametric; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D015395:Histocompatibility Antigens Class I; C508020:IL2RB protein, human; D053646:Interleukin-2 Receptor beta Subunit; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055607:Receptors, Natural Killer Cell; D011991:Receptors, Virus; C066100:poliovirus receptor