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

Introduction: 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.
Methods: 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 ^dim 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.
Results: ILT2-positive CD56 ^dim NK cells in PBMCs were increased in HCC patients compared with HVs. In HCC patients, ILT2-positive CD56 ^dim 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 ^dim NK cells from HCC patients was inhibited by masking antibodies against MIF and CXCR4. ILT2-positive CD56 ^dim NK cells exhibited lower capacities for cytotoxicity and ADCC than ILT2-negative cells, which were partially restored by ILT2 blockade.
Conclusions: In HCC patients, ILT2 is a signature molecule for cancerous CD56 ^dim NK cells with impaired cytolytic capacity. The MIF-CXCR4 interaction is associated with ILT2 induction on CD56 ^dim NK cells and ILT2 serves as a target for functional NK cell restoration.
Competing Interests: SY has received a lecture fee from Gilead Sciences. TI has received lecture fees from Chugai Pharmaceutical Co., Ltd. and AstraZeneca, and a research grant from Chugai Pharmaceutical Co., Ltd. HT has received lecture fees from Gilead Sciences, AbbVie, Eisai, Fujifilm WAKO, Terumo, Kowa, Takeda and AstraZeneca. TKK has received lecture fees from Janssen Pharmaceutical, Taisho Pharmaceutical, Kowa Company, Otsuka Pharmaceutical, Eisai, ASKA Pharmaceutical, AbbVie, and EA Pharma. AT has received a research grant from Ono Pharmaceutical Co. TTK has received lecture fees from Gilead Sciences and AbbVie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
(Copyright © 2024 Sakata, Yoshio, Yamazoe, Mori, Kakazu, Aoki, Aoyanagi, Okamoto, Ito, Toyoda, Kawaguchi, Ono, Takahashi, Taketomi and Kanto.)