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

Sep 21, 2026

Natural killer (NK) cells are central to immune surveillance in the liver, yet patients with hepatocellular carcinoma (HCC) show impaired anti-tumor activity. The study investigates ILT2 expression on NK cell subsets, comparing natural killer cell phenotypes and functions between age-matched healthy volunteers and HCC patients. ILT2-positive CD56dim NK cells increase in HCC and exhibit reduced cytotoxicity and ADCC, associated with MIF-CXCR4-driven ILT2 induction. Blocking ILT2 partially restores NK functional capacity, supporting ILT2 as a therapeutic target for NK restoration in HCC.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Methods

Results

Conclusions

TYPE Original Research PUBLISHED 04 April 2024 DOI 10.3389/fimmu.2024.1389411 OPEN ACCESS EDITED BY Margherita Doria, Bambino Gesù Children ’s Hospital (IRCCS), Italy REVIEWED BY Shahrokh Abdolahi, Shahid Beheshti University of Medical Sciences, Iran Marc Delcommenne, MBL International, United States *CORRESPONDENCE Sachiyo Yoshio [sachiyo@hospk.ncgm.go.jp](sachiyo@hospk.ncgm.go.jp) RECEIVED 21 February 2024 ACCEPTED 25 March 2024 PUBLISHED 04 April 2024 CITATION Sakata T, Yoshio S, Yamazoe T, Mori T, Kakazu E, Aoki Y, Aoyanagi N, Okamoto T, Ito T, Toyoda H, Kawaguchi T, Ono Y, Takahashi Y, Taketomi A and Kanto T (2024) Immunoglobulin-like transcript 2 as an impaired anti-tumor cytotoxicity marker of natural killer cells in patients with hepatocellular carcinoma. Front. Immunol. 15:1389411 . doi: 10.3389/fimmu.2024.1389411 COPYRIGHT © 2024 Sakata, Yoshio, Yamazoe, Mori, Kakazu, Aoki, Aoyanagi, Okamoto, Ito, Toyoda, Kawaguchi, Ono, Takahashi, Taketomi and Kanto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Immunoglobulin-like transcript 2 as an impaired anti-tumor cytotoxicity marker of natural killer cells in patients with hepatocellular carcinoma Toshihiro Sakata 1,2, Sachiyo Yoshio1*, Taiji Yamazoe 1, Taizo Mori 1, Eiji Kakazu 1, Yoshihiko Aoki 3, Nobuyoshi Aoyanagi 3, Toru Okamoto 4, Takanori Ito 5, Hidenori Toyoda 6, Takumi Kawaguchi 7, Yoshihiro Ono 8, Yu Takahashi 8, Akinobu Taketomi 2 and Tatsuya Kanto 1 1 Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan, 2 Department of Gastoenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido, Japan, 3 Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan, 4 Department of Microbiology, Juntendo University School of Medicine, Tokyo, Japan, 5 Division of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan, 6 Department of Gastroenterology, Ogaki Municipal Hospital, Gifu, Japan, 7 Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan, 8 Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 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 CD56dim 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 CD56dim NK cells in PBMCs were increased in HCC patients compared with HVs. In HCC patients, ILT2-positive CD56dim 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 CD56dim NK cells from HCC patients was inhibited by masking antibodies against MIF and CXCR4 . ILT2-positive CD56dim

FAQs

What is the main purpose of the study in HCC patients?

To identify functional targets on NK cells by characterizing ILT2 expression and its relationship with impaired anti-tumor cytotoxicity in hepatocellular carcinoma.

How were NK cell phenotypes and functions evaluated?

NK cells were analyzed in blood mononuclear cells (PBMCs) and intrahepatic lymphocytes (IHLs) from cancerous and non-cancerous tissues, and cytotoxicity and ADCC were tested in vitro.

What did the results show about ILT2-positive CD56dim NK cells?

ILT2-positive CD56dim NK cells were increased in HCC patients, and these cells showed lower cytotoxic and ADCC capacities than ILT2-negative cells, with partial restoration after ILT2 blockade.

Sep 21, 2026

Uploaded by Emma Wilson