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MICA triggering signal for NK cell tumor lysis is counteracted by HLA‐G1‐mediated inhibitory signal
Author(s) -
Menier Catherine,
Riteau Béatrice,
Carosella Edgardo D.,
RouasFreiss Nathalie
Publication year - 2002
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.10460
Subject(s) - cytolysis , nkg2d , mhc class i , biology , microbiology and biotechnology , cytotoxicity , lymphokine activated killer cell , major histocompatibility complex , human leukocyte antigen , cell culture , janus kinase 3 , cell , cancer research , antigen , immunology , interleukin 21 , t cell , in vitro , immune system , biochemistry , genetics
MICA, a highly glycosylated membrane‐anchored cell–surface MHC Class I‐related chain, has recently been reported to activate NK cell cytolytic responses in epithelial tumors. Tumor cells may escape from NK lysis by counteracting NK cytotoxicity activating signals with inhibitory ones. Among the molecules that mediate an NK inhibitory signal, HLA‐G1, a non‐classical MHC Class I antigen, is of particular interest. HLA‐G1 is ectopically expressed in various tumors, including melanoma and constitutes the major NK inhibitory ligand in the M8 melanoma cell line when coexpressed with HLA‐A, ‐B, ‐C and ‐E molecules. We have evaluated the balance between 2 powerful signals that affect NK cell tumor lysis, one inhibitory and the other one activating, respectively HLA‐G1 and MICA. For this purpose, we transfected the M8 melanoma cell line, which spontaneously expresses MICA, with HLA‐G1 cDNA, using it as a target for the NKL effector. We carried out cytotoxicity assays, using antibodies that disrupt interactions between the MICA and HLA‐G1 ligands and their respective NK effector counterparts, the NKG2D activating and ILT2 inhibitory receptors. Results showed that 1) MICA expressed in the M8 melanoma cell line triggered NK cell tumor lysis and 2) HLA‐G1 coexpression mediated the inhibition of NK cytotoxicity by mitigating the MICA activating signal. HLA‐G1 expression in a tumor cell line in which MICA is switched on would therefore appear to be a powerful way to turn off NK cells, supporting the emerging idea that the balance between positive and negative NK cytolysis signals critically influences tumor progression. © 2002 Wiley‐Liss, Inc.