AUTHOR=Sakata Toshihiro , Yoshio Sachiyo , Yamazoe Taiji , Mori Taizo , Kakazu Eiji , Aoki Yoshihiko , Aoyanagi Nobuyoshi , Okamoto Toru , Ito Takanori , Toyoda Hidenori , Kawaguchi Takumi , Ono Yoshihiro , Takahashi Yu , Taketomi Akinobu , Kanto Tatsuya 

TITLE=Immunoglobulin-like transcript 2 as an impaired anti-tumor cytotoxicity marker of natural killer cells in patients with hepatocellular carcinoma

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1389411

DOI=10.3389/fimmu.2024.1389411

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Natural killer (NK) cells play a pivotal role in immune surveillance in the liver. We aimed to identify potential targets for NK cell-mediated immune intervention by revealing the functional molecules on NK cells in HCC patients.</p></sec><sec><title>Methods</title><p>To evaluate the impact of aging on NK cell phenotypes, we examined NK cells from healthy volunteers (HVs) of various ages. Because ILT2 expression on CD56<sup>dim</sup> NK cells increased with increasing age, we enrolled age-matched HCC patients and HVs. We determined the NK cell phenotypes in blood mononuclear cells (PBMCs) and intrahepatic lymphocytes (IHLs) from cancerous and non-cancerous tissues. We evaluated cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) of NK cells in vitro.</p></sec><sec><title>Results</title><p>ILT2-positive CD56<sup>dim</sup> NK cells in PBMCs were increased in HCC patients compared with HVs. In HCC patients, ILT2-positive CD56<sup>dim</sup> NK cells were increased in cancerous IHLs compared with non-cancerous IHLs and PBMCs. We examined the impact of macrophage migration inhibitory factor (MIF) on ILT2 expression in co-cultures of HCC cells and NK cells. The enhanced expression of ILT2 on CD56<sup>dim</sup> NK cells from HCC patients was inhibited by masking antibodies against MIF and CXCR4. ILT2-positive CD56<sup>dim</sup> NK cells exhibited lower capacities for cytotoxicity and ADCC than ILT2-negative cells, which were partially restored by ILT2 blockade.</p></sec><sec><title>Conclusions</title><p>In HCC patients, ILT2 is a signature molecule for cancerous CD56<sup>dim</sup> NK cells with impaired cytolytic capacity. The MIF-CXCR4 interaction is associated with ILT2 induction on CD56<sup>dim</sup> NK cells and ILT2 serves as a target for functional NK cell restoration.</p></sec>