title: Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma.
abstract: The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis.
  
  
  
  Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study.
  
  
  
  Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells.
  
  
  
  The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Marta
authors.initials: M
authors.lastname: Garnelo
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Alex
authors.initials: A
authors.lastname: Tan
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR, Biopolis, Singapore.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Her
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors.forename: Joe
authors.initials: J
authors.lastname: Yeong
authors.affiliation: SingHealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singapore, Singapore.
authors.forename: Chun Jye
authors.initials: CJ
authors.lastname: Lim
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Jinmiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors.forename: Kiat Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: National Cancer Centre, Singapore, Singapore.|Singapore General Hospital, Singapore, Singapore.|Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Pierce
authors.initials: P
authors.lastname: Chow
authors.affiliation: National Cancer Centre, Singapore, Singapore.|Singapore General Hospital, Singapore, Singapore.
authors.forename: Alexander
authors.initials: A
authors.lastname: Chung
authors.affiliation: National Cancer Centre, Singapore, Singapore.|Singapore General Hospital, Singapore, Singapore.|Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: London Lucien Pj
authors.initials: LL
authors.lastname: Ooi
authors.affiliation: National Cancer Centre, Singapore, Singapore.
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
authors.affiliation: Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Virology, Technical University München/Helmholtz Zentrum München, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong.
authors.forename: Irene O L
authors.initials: IO
authors.lastname: Ng
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nardin
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR, Biopolis, Singapore.|National Cancer Centre, Singapore, Singapore.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Abastado
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|SingHealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singapore, Singapore.|Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Valerie
authors.initials: V
authors.lastname: Chew
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D018941:Antigens, CD19 / Q000235:genetics; D018951:Antigens, CD20 / Q000032:analysis; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D017252:CD3 Complex / Q000032:analysis; D019013:CD40 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D053148:Caspase 3 / Q000032:analysis; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D053804:Granzymes / Q000032:analysis; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D019394:Ki-67 Antigen / Q000032:analysis; D008113:Liver Neoplasms / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010641:Phenotype; D012189:Retrospective Studies; D015996:Survival Rate; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D018941:Antigens, CD19; D018951:Antigens, CD20; D017252:CD3 Complex; D019013:CD40 Antigens; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D019394:Ki-67 Antigen; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D007371:Interferon-gamma; D051997:ADP-ribosyl Cyclase 1; D053804:Granzymes; D053148:Caspase 3
keywords: B CELL; CANCER IMMUNOBIOLOGY; HEPATOCELLULAR CARCINOMA; IMMUNOREGULATION; T LYMPHOCYTES