Tumor-derived soluble MICs impair CD3(+)CD56(+) NKT-like cell cytotoxicity in cancer patients.
Upon ligation with its ligands, the activating receptor NKG2D stimulates or costimulates CD8(+) T cells or NK cells. The inducible gene MHC class I chain-related molecules (MICs), which belong to the NKG2D ligand family and usually initiate the process of lymphocyte activation, have been found to be broadly expressed on epithelial tumor cells. Sustained localized expression or release of soluble forms of MICs (sMICs) by tumor cells play key roles in tumor evasion via the impairment of T cell and NK cell functions. NKG2D is also expressed on the surface of CD3(+)CD56(+) NKT-like cells, which participate in tumor rejection via direct cytolysis. We speculated whether sMICs have the same impact on NKT-like cells. In this study, we demonstrated that in vitro killing by freshly isolated NKT-like cells was principally mediated by NKG2D, and the cytotoxic function of NKT-like cells isolated from cancer patients was obviously compromised. We found a significant correlation between elevated tumor-derived sMICs and down-modulation of NKG2D expression on NKT-like cell surfaces in human ovarian cancer and prostate cancer patients. We determined that elevated serum sMIC impairs the lytic activity via downregulation of the NKG2D receptor because incubation of NKT-like cells with sera obtained from cancer patients down-modulated surface NKG2D expression, whereas the addition of neutralizing anti-MIC mAbs restored surface NKG2D expression. We suggest that tumors shedding MICs may promote immune evasion by impairing NKT-like cell cytotoxicity.
Wang
Huiming
H
Institute of immunology, PLA, The Third Military Medical University, Chongqing 400038, PR China.
Yang
Di
D
Xu
Wenyue
W
Wang
Yiqin
Y
Ruan
Zhihua
Z
Zhao
Tingting
T
Han
Junfeng
J
Wu
Yuzhang
Y
D017252:CD3 Complex / Q000276:immunology*; D019002:CD56 Antigen / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D008297:Male; D055611:Natural Killer T-Cells / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000503:physiopathology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000503:physiopathology*; D014407:Tumor Cells, Cultured
D017252:CD3 Complex; D019002:CD56 Antigen; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C423230:ULBP2 protein, human