title: Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment options. As the status of the tumour immune microenvironment can affect progression of established tumours, we evaluated potential immune mechanisms associated with survival in HCC.
  
  
  METHODS
  Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes (TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis and proliferation).
  
  
  RESULTS
  The immune microenvironment within tumours was found to be heterogeneous, although globally more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and exclusively in areas devoid of proliferating tumour cells. NK and CD8(+) T cell densities are correlated positively with tumour apoptosis, and negatively with tumour proliferation.
  
  
  CONCLUSIONS
  Hence, an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Immunos #04-00, 8A Biomedical Grove, Singapore.
authors.forename: Valerie
authors.initials: V
authors.lastname: Chew
authors.forename: Charlene
authors.initials: C
authors.lastname: Tow
authors.forename: Marissa
authors.initials: M
authors.lastname: Teo
authors.forename: Hing Lok
authors.initials: HL
authors.lastname: Wong
authors.forename: Jasmine
authors.initials: J
authors.lastname: Chan
authors.forename: Adam
authors.initials: A
authors.lastname: Gehring
authors.forename: Marie
authors.initials: M
authors.lastname: Loh
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bolze
authors.forename: Richard
authors.initials: R
authors.lastname: Quek
authors.forename: Victor K M
authors.initials: VK
authors.lastname: Lee
authors.forename: Kang Hoe
authors.initials: KH
authors.lastname: Lee
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Abastado
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nardin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007107:Immune System / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018932:Chemokine CCL2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha