title: Liver-infiltrating CD8(+) lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma.
abstract: BACKGROUND
  Chronic liver inflammation and immune/inflammatory response promote hepatocellular carcinoma. The aim of this study was to characterize the immune status of HCV-related cirrhosis in patients with hepatocellular carcinoma (HCV-HCC) as compared to HCV patients without hepatocellular carcinoma.
  
  
  METHODS
  Immune markers (CD3, CD4, CD8, CD20, CD56, TCRγδ, FoxP3) and gene expression profiles (CD8α, CD8β, FoxP3, IL-6, IFN-γ, perforin, RANTES) were analysed in a test cohort by immunohistochemistry and quantitative RT-PCR analysis on serial non-tumorous and tumorous tissues.
  
  
  RESULTS
  Immune micro-environment was more inflammatory in HCV-HCC than HCV cirrhotic livers. The number of CD3(+) , CD4(+) , CD8(+) and CD20(+) liver-infiltrating lymphocytes was significantly higher, whereas the number of CD56(+) cells was significantly lower in HCV-HCC compared to HCV cirrhotic parenchyma. These differences were restricted to fibrous septa for CD4(+) and CD20(+) cells and to nodular parenchyma for CD8(+) cells. Gene expressions of CD8α, FoxP3 and RANTES were also significantly higher in HCV-HCC than in HCV cirrhosis. Interestingly, in a large cohort of 63 HCV-HCC patients. The number of CD8(+) cells ≥100/field was associated with significant higher tumour recurrence (P = 0.003) and lower overall survival (P = 0.05) at 5 years.
  
  
  CONCLUSIONS
  High densities of liver-infiltrating lymphocytes in HCV-HCC cirrhotic parenchyma prevail inflammatory conditions and could contribute to tumorigenesis and tumour recurrence. These results could contribute towards better clinical evaluation of patients susceptible for HCC recurrence after curative surgery.
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ramzan
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.|Département d'Anatomie et de Cytologie Pathologiques, CHU de Grenoble, Grenoble, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sturm
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.|Clinique d' Hépatogastroentérologie, pôle DigiDune, CHU de Grenoble, Grenoble, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Decaens
authors.affiliation: Service d'Anatomie et de Cytologie Pathologiques, Hôpital Pellegrin, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: Service de Pathologie, Hôpital de la Croix Rousse, Lyon, France.|Université Claude Bernard Lyon 1, INSERM UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Hospices Civils de Lyon, Lyon, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bancel
authors.affiliation: Université Claude Bernard Lyon 1, INSERM UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Hospices Civils de Lyon, Lyon, France.|Service d'Hépatologie, Hôpital de la Croix-Rousse, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Merle
authors.affiliation: Département de Pathologie, APHP, Groupe Hospitalier Henri Mondor, Val de Marne, Université Paris Est-Créteil, Créteil, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Tran Van Nhieu
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Slama
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.|Clinique de Chirurgie Digestive, pôle DIGIDUNE, CHU de Grenoble, Grenoble, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Letoublon
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.|Clinique d' Hépatogastroentérologie, pôle DigiDune, CHU de Grenoble, Grenoble, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Zarski
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jouvin-Marche
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.|Clinique d' Hépatogastroentérologie, pôle DigiDune, CHU de Grenoble, Grenoble, France.
authors.forename: Patrice N
authors.initials: PN
authors.lastname: Marche
authors.affiliation: INSERM, Unité 823, Grenoble, France.|Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.|Clinique d' Hépatogastroentérologie, pôle DigiDune, CHU de Grenoble, Grenoble, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroy
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005260:Female; D005602:France; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000032:analysis; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D018836:Inflammation Mediators
keywords: hepatitis C Virus; hepatocellular carcinoma; liver-infiltrating lymphocytes; natural Killer cell