Microbiota, Inflammation and Cancer

Nicolas MONIAUX Sylvie JOB

Hôpital Paul Brousse Paris-Saclay

Introduction

Primary liver cancers develop within a complex microenvironment where tumor cells closely interact with immune cells, stromal cells, and the extracellular matrix. This microenvironment is strongly influenced by the digestive tract, the main reservoir of the gut microbiota, whose bacterial derivatives transit to the liver via the gut–liver axis. These bacteria and their metabolites can modulate the tumor immune phenotype, influencing local immunity, tumor tolerance, and response to therapies.

Objectives

Our team studies the tumor microenvironment and its role in immune tolerance in primary liver cancers, particularly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Leveraging our expertise, we analyze interactions between tumor cells, the immune system, and the microbial ecosystem to identify new therapeutic levers. We explore the influence of the gut microbiota, bacterial products, and certain innate immunity effectors on tumor physiology and immunity. The aim is to identify microbial biomarkers and develop innovative strategies to optimize responses to immunotherapies.

Our research is organized around three complementary axes:
(1) Deciphering the mechanisms of hepatic and loco-regional immune tolerance and uncovering their connection with the human microbiota.
(2) Demonstrating the ability of specific microbes or microbial products to overcome tumor-induced immunosuppression in preclinical models.
(3) Investigating the impact of the innate immunity effector REG3A on organ homeostasis and liver carcinogenesis.

Axes [1] [2] [3]

Expertises Publications Team(s) Sponsors

3 research areas

Axis 1 : Deciphering the Mechanisms of Immune Tolerance in Liver Cancers

Tumor immune tolerance is a major barrier to the effectiveness of immunotherapies in primary liver cancers. Using an integrative approach combining immunological, transcriptomic, and metabolomic analyses, our team was among the first to identify and characterize the immune phenotypes and underlying mechanisms of immune tolerance present in ICC and HCC tumors (Job et al., 2020; Shalhoub et al., 2024).

Our current research aims to unravel the complex interactions between the tumor microenvironment, local and systemic immunity, and the gut microbiota, in order to better understand the pathophysiology of these cancers and identify new therapeutic targets.

Leveraging patient cohorts followed at the Hepatobiliary Center (CHB), we focus on three main objectives:

Characterizing tumor immune profiles using immune classification systems we developed for ICC and HCC, to uncover patient-specific mechanisms of immune tolerance.
Studying the composition of the gut and tumor microbiota, identifying commensal bacteria and their metabolites, and analyzing their relationship with tumor immune phenotypes, disease progression, and treatment response.
Deciphering interactions between the microbiota, tumor immunity, and the extracellular matrix in primary liver cancers, to understand how microbial derivatives modulate matrix composition and properties, influence cellular signaling, and contribute to immune tolerance and tumor progression. Special attention is given to innate immunity effectors, notably the antioxidant lectin REG3A, as mediators of these interactions and potential targets for novel therapeutic strategies.

This work enables the identification of metagenomic and immunological biomarkers predictive of immunotherapy response and paves the way for personalized medicine approaches, which will be further validated in preclinical models in Axis 2.

axe 1

Axis 2 : Harnessing the Immunomodulatory Potential of the Microbiota to Overcome Tumor Immune Tolerance and Enhance Treatment Response

The gut microbiota directly influences the progression of primary liver cancers, notably via the portal circulation and the immune interface. While its role is well established in chronic liver diseases such as metabolic steatohepatitis (MASH), its impact on liver carcinogenesis remains insufficiently characterized.

Our goal is to explore the potential of microbial regulators to reshape the immunosuppressive tumor microenvironment into an immunoactive phenotype capable of slowing tumor progression. Our work has already highlighted the central role of REG3A, an antimicrobial and antioxidant peptide from innate immunity, in controlling microbial diversity and the production of immunomodulatory metabolites. These properties position REG3A as a promising therapeutic lever to overcome tumor immune tolerance and restore treatment efficacy (Moniaux et al., 2024; Darnaud et al., 2018).

Within this framework, we aim to experimentally demonstrate the causal role of the intestinal microbiota and its derivatives in:

The initiation and progression of liver cancers, using murine models that recapitulate the immune subtypes identified in humans (Axis 1).
Modulating the tumor immune ecosystem, including lymphocyte infiltration and immune checkpoint expression.
Optimizing therapeutic strategies, by testing the capacity of specific microbial metabolites (e.g., butyrate, LPS) and innate immunity peptides (such as REG3A) to restore effective antitumor immunity.

axe 2

Axis 3 : Understanding the Role of REG3A, a Key Innate Immunity Effector at the Interface of Nutritional Metabolism, Gut Microbiota, Organ Homeostasis, and Liver Carcinogenesis

REG3A is a C-type lectin and innate immunity effector with antioxidant properties that allows it to trap reactive oxygen species (ROS). It plays a central role at the interface between the gut microbiota and organ homeostasis, acting both on the host and its commensal flora. Our research has highlighted several key functions of REG3A:

Regulation of the gut microbiota: REG3A shapes bacterial composition by conferring anti-inflammatory properties to the microbiota. In particular, it protects oxygen-sensitive Gram-positive anaerobes from oxidative damage, contributing to an intestinal environment conducive to immune tolerance (Darnaud et al., 2018).
Energy metabolism and metabolic diseases: REG3A improves glucose homeostasis and insulin sensitivity by maintaining the integrity of GP130/AMPK signaling in skeletal muscle. It also limits the progression of liver metabolic disorders, including steatosis, NASH, and fibrosis (Gonzalez et al., 2023).
Tumor suppressor function: In hepatocellular carcinoma (HCC), REG3A acts as a tumor suppressor by reducing UDP-GlcNAc availability, thereby limiting protein O-GlcNAcylation—a post-translational modification that promotes liver carcinogenesis (Moniaux et al., 2024).

Perspectives

Our future work aims to unravel the mechanisms through which REG3A modulates the interactions between the microbiota, metabolome, and hepatic immune ecosystem, in the context of nutrition-related metabolic disease and primary liver cancers. We will focus on two main directions:

Analyzing functional communication between the REG3A-shaped gut microbiota, its metabolic derivatives, and local hepatic immunity, to better understand their role in establishing or overcoming tumor immune tolerance.
Investigating the impact of REG3A on the composition and oxidative state of the hepatic extracellular matrix (ECM), and determining how these changes influence cellular signaling, inflammation, and tumor progression.

axe 3

These studies rely on an integrative, translational approach, combining metagenomic, transcriptomic, metabolomic, and immunological analyses, in close collaboration with clinicians and biotechnology companies specializing in immunotherapy.

Ultimately, this research could lead to the development of combined therapeutic strategies that integrate microbiota modulation and immunotherapy, with the potential to significantly improve the management of patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC).