Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients.
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.
Chew
Valerie
V
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Immunos #04-00, 8A Biomedical Grove, Singapore.
Tow
Charlene
C
Teo
Marissa
M
Wong
Hing Lok
HL
Chan
Jasmine
J
Gehring
Adam
A
Loh
Marie
M
Bolze
Alexandre
A
Quek
Richard
R
Lee
Victor K M
VK
Lee
Kang Hoe
KH
Abastado
Jean-Pierre
JP
Toh
Han Chong
HC
Nardin
Alessandra
A
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
D014408:Biomarkers, Tumor; D018932:Chemokine CCL2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha