Kill and Clearance in HCC: An Approach Based on NK Cells and Macrophages

Abstract

In our previous perspective, we investigated the role of hypoxic lesions in the development of necrotic zone in solid tumors (1). We suggested the increased infiltration of macrophages/monocytes to the pre-necrotic zone and under the influence of chemoattractants (VEGF, CCL2, and CCL5), danger signals, and a trail of necrotic debris as a mechanism to maximize their opportunity to clear the lesion. They continuously sample and mediates recognition of damage-associated molecular patterns (DAMPs), including heat shock proteins, cytokines, DNA, RNA, metabolic ATP, HMGB1, histones, altered carbohydrate, and negatively exposed phosphatidylserine (PS) on the surface of necrotic corpses or apoptotic cells. We suggested gradual alteration of gene expression in macrophages eventually turns off their phagocytic machinery leaving uncleared cell corpses as a rich source of building blocks for cancer stem cells. Even subtle differences in the internalized ligands could have far-reaching consequences on cytokine production and antigen presentation to NK cells. Here, we propose a synergistic act of kill and clearance by NK cells and macrophages as a therapeutic strategy in HCC. We have provided a comprehensive mechanism underlying human NK cell and macrophage dysfunction in HCC, investigated the crosstalk between NK cells and a group of myeloid-derived suppressor cells (MDSCs) with a typical monocytic phenotype (CD14+ HLA-DR-/low), and the immunosuppressive role of hypoxia in HCC. We have also outlined the possible future research directions to target the crosstalk between NK cells and macrophage/MDSC to enhance kill and clearance by NK cells and macrophages in HCC and other solid tumors.