Early Hepatic Lesions Display Immature Tertiary Lymphoid Structures and Show Elevated Expression of Immune Inhibitory and Immunosuppressive Molecules

Maxime Meylan, Florent Petitprez, Laetitia Lacroix, Luca Di Tommaso, Massimo Roncalli, Antoine Bougoüin, Alexis Laurent, Giuliana Amaddeo, Daniele Sommacale, Hélène Regnault, Jonathan Derman, Cécile Charpy, Fouad Lafdil, Jean-Michel Pawlotsky, Catherine Sautès-Fridman, Wolf H Fridman, Julien Calderaro

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: The impact of tertiary lymphoid structures (TLS) in hepatocellular carcinoma (HCC) progression is being extensively investigated. However, their presence during the early steps of human liver carcinogenesis remains unknown. We thus aimed to determine whether TLS are induced in preneoplastic/early hepatic lesions (EHL), and whether they are associated with a particular immune profile.

EXPERIMENTAL DESIGN: A series of 127 EHLs (low/high-grade dysplastic nodules, early HCC, and small and progressed HCC) was included in the study. TLSs were investigated by pathologic reviewing. Densities of immune cells were assessed using IHC. A subset of lesions was microdissected and gene expression profiling was performed with a custom NanoString panel.

RESULTS: Compared with surrounding cirrhotic nodules, EHL of all stages displayed increased densities of T cells, B cells, and dendritic cells. Immature TLSs were identified in 24% of EHL. Gene expression profiling identified a subset of EHL with elevated mRNA levels of various cytokines involved in immune cells' recruitment and TLS induction. This subgroup of EHL also showed overexpression of genes related to T- and B-cells' activation and antigen presentation, as well as those related to immunosuppression and immune exhaustion.

CONCLUSIONS: Local immune activation occurs in the very early steps of liver carcinogenesis; however, it may not be fully efficient and paradoxically favor immune evasion and progression to full-blown HCC. These results have implications for the development of anti-HCC chemopreventive strategies in cirrhotic patients.

Original languageEnglish
Pages (from-to)4381-4389
Number of pages9
JournalClin. Cancer Res.
Volume26
Issue number16
DOIs
Publication statusPublished - Aug 15 2020

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