Mathilde Cadoux1, Stefano Caruso2, Sandrine Pham1, Angélique Gougelet3, Céline Pophillat1, Rozenn Riou3, Robin Loesch3, Sabine Colnot3, Công Trung Nguyen4, Julien Calderaro4, Séverine Celton-Morizur1, Nadia Guerra5, Jessica Zucman-Rossi2, Chantal Desdouets1, Jean-Pierre Couty6. 1. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France. 2. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Functional genomics of solid tumors Team, Labex Immuno-Oncology, Paris, France. 3. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Oncogenic functions of β-catenin signalling in the liver team F-75006 Paris, France. 4. Institut Mondor de Recherche Biomédicale, INSERM U955, Créteil, France. 5. Department of Life Sciences, Imperial College London, London, United Kingdom. 6. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France. Electronic address: jean-pierre.couty@inserm.fr.
Abstract
BACKGROUND & AIMS: The NKG2D system is a potent immunosurveillance mechanism in cancer, wherein the activating NK cell receptor (NKG2D) on immune cells recognises its cognate ligands on tumour cells. Herein, we evaluated the expression of NKG2D ligands in hepatocellular carcinoma (HCC), in both humans and mice, taking the genomic features of HCC tumours into account. METHODS: The expression of NKG2D ligands (MICA, MICB, ULBP1 and ULBP2) was analysed in large human HCC datasets by Fluidigm TaqMan and RNA-seq methods, and in 2 mouse models (mRNA and protein levels) reproducing the features of both major groups of human tumours. RESULTS: We provide compelling evidence that expression of the MICA and MICB ligands in human HCC is associated with tumour aggressiveness and poor patient outcome. We also found that the expression of ULBP1 and ULBP2 was associated with poor patient outcome, and was downregulated in CTNNB1-mutated HCCs displaying low levels of inflammation and associated with a better prognosis. We also found an inverse correlation between ULBP1/2 expression levels and the expression of β-catenin target genes in patients with HCC, suggesting a role for β-catenin signalling in inhibiting expression. We showed in HCC mouse models that β-catenin signalling downregulated the expression of Rae-1 NKG2D ligands, orthologs of ULBPs, through TCF4 binding. CONCLUSIONS: We demonstrate that the expression of NKG2D ligands is associated with aggressive liver tumorigenesis and that the downregulation of these ligands by β-catenin signalling may account for the less aggressive phenotype of CTNNB1-mutated HCC tumours. LAY SUMMARY: The NKG2D system is a potent immunosurveillance mechanism in cancer. However, its role in hepatocellular carcinoma development has not been widely investigated. Herein, we should that the expression of NKG2D ligands by tumour cells is associated with a more aggressive tumour subtype.
BACKGROUND & AIMS: The NKG2D system is a potent immunosurveillance mechanism in cancer, wherein the activating NK cell receptor (NKG2D) on immune cells recognises its cognate ligands on tumour cells. Herein, we evaluated the expression of NKG2D ligands in hepatocellular carcinoma (HCC), in both humans and mice, taking the genomic features of HCC tumours into account. METHODS: The expression of NKG2D ligands (MICA, MICB, ULBP1 and ULBP2) was analysed in large human HCC datasets by Fluidigm TaqMan and RNA-seq methods, and in 2 mouse models (mRNA and protein levels) reproducing the features of both major groups of human tumours. RESULTS: We provide compelling evidence that expression of the MICA and MICB ligands in human HCC is associated with tumour aggressiveness and poor patient outcome. We also found that the expression of ULBP1 and ULBP2 was associated with poor patient outcome, and was downregulated in CTNNB1-mutated HCCs displaying low levels of inflammation and associated with a better prognosis. We also found an inverse correlation between ULBP1/2 expression levels and the expression of β-catenin target genes in patients with HCC, suggesting a role for β-catenin signalling in inhibiting expression. We showed in HCC mouse models that β-catenin signalling downregulated the expression of Rae-1 NKG2D ligands, orthologs of ULBPs, through TCF4 binding. CONCLUSIONS: We demonstrate that the expression of NKG2D ligands is associated with aggressive liver tumorigenesis and that the downregulation of these ligands by β-catenin signalling may account for the less aggressive phenotype of CTNNB1-mutated HCC tumours. LAY SUMMARY: The NKG2D system is a potent immunosurveillance mechanism in cancer. However, its role in hepatocellular carcinoma development has not been widely investigated. Herein, we should that the expression of NKG2D ligands by tumour cells is associated with a more aggressive tumour subtype.
Authors: Josep M Llovet; Florian Castet; Mathias Heikenwalder; Mala K Maini; Vincenzo Mazzaferro; David J Pinato; Eli Pikarsky; Andrew X Zhu; Richard S Finn Journal: Nat Rev Clin Oncol Date: 2021-11-11 Impact factor: 65.011