Author Correction: Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Dudek, Michael; Pfister, Dominik; Donakonda, Sainitin; Filpe, Pamela; Schneider, Annika; Laschinger, Melanie; Hüser, Norbert; Meiser, Philippa; Bayerl, Felix; Inverso, Donato; Wigger, Jennifer; Sebode, Marcial; Öllinger, Rupert; Rad, Roland; Hegenbarth, Silke; Anton, Martina; Guillot, Adrien; Bowman, Andrew P.; Heide, Danijela; Müller, Florian; Ramadori, Pierluigi; Leone, Valentina; García‐Cáceres, Cristina; Gruber, Tim; Seifert, Gabriel; Kabat, Agnieszka M.; Mallm, Jan‐Philipp; Reider, Simon; Effenberger, Maria; Roth, Susanne; Billeter, Adrian T.; Müller-Stich, Beat; Pearce, Edward J.; Koch‐Nolte, Friedrich; Käser, Rafael; Tilg, Herbert; Thimme, Robert; Böettler, Tobias; Tacke, Frank; Dufour, Jean‐François; Haller, Dirk; Murray, Peter J.; Heeren, Ron M. A.; Zehn, Dietmar; Böttcher, Jan; Heikenwälder, Mathias; Knolle, Percy

doi:10.1038/s41586-021-03568-2

Cited by 5 publications

(7 citation statements)

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“…Also, when cryptogenic HCC was included in the NAFLD/NASH group, both PFS and OS were better in those patients (median PFS: 9.3 vs. 7.5 months, P = 0.012) (median OS: 21.0 vs. 16.9 months, P < 0.001). An interesting meta-analysis article recently reported by Pfister showed that patients with a viral etiology demonstrated therapeutic benefits with ICI treatment [HR 0.64], whereas those with nonviral etiology HCC did not [HR 0.92] (P = 0.03) 5 . That report also presented results of two different validation studies of ICI treatment for HCC, in which NAFLD-HCC cases showed significantly worse OS than cases of HCC with another etiology (HR 2.6, 95% CI 1.2–5.6, P = 0.017; median 8.8 vs. 17.7 months, P = 0.034).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the good therapeutic response noted for Atezo + Bev in the IMbrave 150 trial, a recent report noted that therapeutic responses to ICI treatments differed according to the etiology of the background liver disease 5 . A meta-analysis of findings in that study indicated that patients with HCC with a viral etiology showed therapeutic benefits from ICI use [HR 0.64], whereas those with a nonviral etiology did not [HR 0.92] (P = 0.03).…”

Section: Introductionmentioning

confidence: 97%

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Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study

Hiraoka

Kumada

Tada

et al. 2021

Sci Rep

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It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child–Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study

Hiraoka

Kumada

Tada

et al. 2021

Sci Rep

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“…Further, by using scRNA-seq, Dudek et al detected the hepatic accumulation of a conserved and expanded CD8+ T cell population marked by CXCR6, PD-1, and granzyme B, which triggered the auto-aggression of killing hepatocytes via Fas-FasL interactions. 32 Specific subclusters of activated hepatic stellate cells (HSCs) featured by the expression of ACTA2 and RBP1 were identified to contribute to the fibrosis of NASH through collagen deposition. 29 Single-cell secretome gene analysis identified HSCs to secrete stellakines associated with chronic liver injury.…”

Section: Signatures Of the Nafld Disease Spectrummentioning

confidence: 99%

Multidimensional landscape of non‐alcoholic fatty liver disease‐related disease spectrum uncovered by big omics data: Profiling evidence and new perspectives

et al. 2023

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Characterized by hepatic lipid accumulation, non‐alcoholic fatty liver disease (NAFLD) is a multifactorial metabolic disorder that could promote the progression of non‐alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Benefiting from recent advances in omics technologies, such as high‐throughput sequencing, voluminous profiling data in HCC‐integrated molecular science into clinical medicine helped clinicians with rational guidance for treatments. In this review, we conclude the majority of publicly available omics data on the NAFLD‐related disease spectrum and bring up new insights to inspire next‐generation therapeutics against this increasingly prevalent disease spectrum in the post‐genomic era.

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“…Oxidative stress in the liver is especially detrimental as it can play a role in cellular dysfunction, injury, and even cell death ( 11 – 13 ). With the advancement of single cell RNA sequence, current studies have identified multiple subsets of CD8 + T cells in human and mouse models of NAFLD ( 9 , 14 ). Resident pathogenic CD8 + T cells in NASH are classified as auto-aggressive toward hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

“…This subset is characterized by expressing high levels of CXCR6, cytotoxicity (granzyme), and exhaustion marker PD-1. However, the hepatic CD8 + T cells were discovered to act in an antigen-independent manner relying on IL-15 driven transcriptional reprogramming and metabolic signals acetate and ATP for activation ( 14 ). Additionally, a subset of CD8 + T cells during NASH resolution operate in a CCR5-dependent chemoattractant manner also relying on IL-15 ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Myeloid cell MHC I expression drives CD8+ T cell activation in nonalcoholic steatohepatitis

Adams,

Collins,

Williams

et al. 2024

Front. Immunol.

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Background & aimsActivated CD8+ T cells are elevated in Nonalcoholic steatohepatitis (NASH) and are important for driving fibrosis and inflammation. Despite this, mechanisms of CD8+ T cell activation in NASH are largely limited. Specific CD8+ T cell subsets may become activated through metabolic signals or cytokines. However, studies in NASH have not evaluated the impact of antigen presentation or the involvement of specific antigens. Therefore, we determined if activated CD8+ T cells are dependent on MHC class I expression in NASH to regulate fibrosis and inflammation.MethodsWe used H2Kb and H2Db deficient (MHC I KO), Kb transgenic mice, and myeloid cell Kb deficient mice (LysM Kb KO) to investigate how MHC class I impacts CD8+ T cell function and NASH. Flow cytometry, gene expression, and histology were used to examine hepatic inflammation and fibrosis. The hepatic class I immunopeptidome was evaluated by mass spectrometry.ResultsIn NASH, MHC class I isoform H2Kb was upregulated in myeloid cells. MHC I KO demonstrated protective effects against NASH-induced inflammation and fibrosis. Kb mice exhibited increased fibrosis in the absence of H2Db while LysM Kb KO mice showed protection against fibrosis but not inflammation. H2Kb restricted peptides identified a unique NASH peptide Ncf2 capable of CD8+ T cell activation in vitro. The Ncf2 peptide was not detected during fibrosis resolution.ConclusionThese results suggest that activated hepatic CD8+ T cells are dependent on myeloid cell MHC class I expression in diet induced NASH to promote inflammation and fibrosis. Additionally, our studies suggest a role of NADPH oxidase in the production of Ncf2 peptide generation.

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Author Correction: Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Cited by 5 publications

References 0 publications

Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study

Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study

Multidimensional landscape of non‐alcoholic fatty liver disease‐related disease spectrum uncovered by big omics data: Profiling evidence and new perspectives

Myeloid cell MHC I expression drives CD8+ T cell activation in nonalcoholic steatohepatitis

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