Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development

Adrián Bouzas Muñoz,Marta Gómez De Cedrón,Ana Ramírez De Molina,Aurora García Tejedor,José Moisés Laparra Llopis,Juan Antonio Giménez-Bastida,Claudia Monika Haros

doi:10.3390/biomedicines9111633

Abstract

Innate immunity in the tumor microenvironment plays a pivotal role in hepatocarcinoma (HCC) progression. Plant seeds provide serine-type protease inhibitors (SETIs), which can have a significant influence on liver inflammation and macrophage function. To elucidate the influence of SETIs to counter pro-tumorigenic conditions, at the early stages of HCC development, it was used as an established model of diethylnitrosamine/thioacetamide-injured liver fed with a standard diet (STD) or high-fat diet (42%) (HFD). The administration of SETIs improved survival and ameliorated tumor burden via modulation of monocyte-derived macrophages as key effectors involved in diet-induced HCC development. RT-qPCR analyses of hepatic tissue evidenced a diet-independent downregulatory effect of SETIs on the transcripts of CD36, FASN, ALOX15, and SREBP1c; however, animals fed with an STD showed opposing effects for PPAR and NRLP3 levels. These effects were accompanied by a decreased production of IL-6 and IL-17 but increased that of TNF in animals receiving SETIs. Moreover, only animals fed an HFD displayed increased concentrations of the stem cell factor. Overall, SETIs administration decreased the hepatic contents of lysophosphatydilcholine, phosphatidylinositol, phosphatidylcholine, and phosphatidyl ethanolamine. Notably, animals that received SETIs exhibited increased hepatic proportions of CD68+CX3CR1+CD74+ cells and at a higher rate in those animals fed an HFD. Altogether, the data evidence that oral administration of SETIs modulates the tumor microenvironment, improving hepatic innate immune response(s) and favoring a better antitumoral environment. It represents a path forward in developing coadjutant strategies to pharmacological therapies, with either a preventive or therapeutic character, to counter physiopathological conditions at early stages of HCC development.

Highlights

There has been an improvement in the understanding of the genetic pathogenesis of HCC; only a few of the main drivers responsible for tumor initiation and progression have been identified as druggable targets [4]
In view of the pivotal role that tumor microenvironment plays in the natural history of HCC, this study focuses on the potential immunomodulatory role of naturally occurring serine-type protease inhibitors (SETIs) in modulating the pro-tumorigenic microenvironment at early stages of HCC development in metabolic models of diethylnitrosamine/thioacetamide (DEN/TAA)injured livers
Cohorts of HCC-developing mice and age-match animals receiving SETIs were assessed for survival (Figure 1B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is a major health problem with high morbidity and mortality, which often implies immune system disorders and local myeloid infiltration creativecommons.org/licenses/by/ 4.0/). Biomedicines 2021, 9, 1633 in hepatic tissue [1]. Macrophages, as a main type of innate immune effector, can play opposing roles in regulating the tumor microenvironment, cell progression, and severity of the disease according to its different phenotype subtypes. Various risk factors for HCC have been well-defined, including liver damage caused by inflammation and metabolic syndrome [2]. Other cofactors such as innate immune ‘Toll-like’ receptor (TLR)-4 activation and gut microbiota have been involved in the control and promotion of HCC [3]. Recent data suggest that environmental inflammation-associated conditions such as non-alcoholic fatty liver disease (NAFLD) or the severe variant non-alcoholic steatohepatitis (NASH)

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Discussion

Conclusion