Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2020; 26(33): 4900-4918
Published online Sep 7, 2020. doi: 10.3748/wjg.v26.i33.4900
Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells
Michela Anna Polidoro, Joanna Mikulak, Valentina Cazzetta, Ana Lleo, Domenico Mavilio, Guido Torzilli, Matteo Donadon
Michela Anna Polidoro, Ana Lleo, Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
Joanna Mikulak, Valentina Cazzetta, Domenico Mavilio, Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
Joanna Mikulak, Domenico Mavilio, Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
Ana Lleo, Guido Torzilli, Matteo Donadon, Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
Ana Lleo, Department of Internal Medicine, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
Guido Torzilli, Matteo Donadon, Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
Author contributions: Donadon M and Polidoro MA contributed to the conceptualization; Polidoro MA, Mikulak J and Cazzetta V reviewed the literature; Polidoro MA, Mikulak J, Donadon M and Cazzetta V wrote the manuscript; Mavilio D, Lleo A, Donadon M and Torzilli G supervised the manuscript; Mavilio D, Polidoro MA, Torzilli G and Donadon M contributed to the final revision; all authors contributed to the final approval.
Conflict-of-interest statement: All other authors have nothing to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Matteo Donadon, MD, PhD, Assistant Professor, Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, via manzoni, 56, Rozzano 20089, Milan, Italy.
Received: April 30, 2020
Peer-review started: April 30, 2020
First decision: June 13, 2020
Revised: June 24, 2020
Accepted: August 20, 2020
Article in press: August 20, 2020
Published online: September 7, 2020

In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.

Keywords: Primary liver cancer, Natural killer cells, Tumor microenvironment, Hepatocellular carcinoma, Intrahepatic cholangiocarcinoma, Immune cells

Core tip: Natural killer (NK) cells are an important innate immune cell type with high cytotoxic activity, mainly involved in the clearance of virus-infected and tumor cells. Due to their potential anti-tumor activity, NK cells are gaining a deeper attention as a promising strategy for immune-based cancer therapy. Several studies reveal that both in hepatocellular carcinoma and intrahepatic cholangiocarcinoma, NK cells infiltrate within tumors and their high frequency was found to be related with a favorable overall survival in these patients. In this review, the authors summarize the current literature on NK cells and their role in primary liver tumors.