Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma

Abstract

ObjectiveHepatocellular carcinoma (HCC) is a heterogeneous disease with poor prognosis and limited methods for predicting patient survival. The nature of the immune cells that infiltrate tumours is known to impact clinical outcome. However, the molecular events that regulate this infiltration require further understanding. Here the ability of immune genes expressed in the tumour microenvironment to predict disease progression was investigated.MethodsUsing quantitative PCR, the expression of 14 immune genes in resected tumour tissues from 57 Singaporean patients was analysed. The nearest-template prediction method was used to derive and test a prognostic signature from this training cohort. The signature was then validated in an independent cohort of 98 patients from Hong Kong and Zurich. Intratumoural components expressing these critical immune genes were identified by in situ labelling. Regulation of these genes was analysed in vitro using the HCC cell line SNU-182.ResultsThe identified 14 immune-gene signature predicts patient survival in both the training cohort (p=0.0004 and HR=5.2) and the validation cohort (p=0.0051 and HR=2.5) irrespective of patient ethnicity and disease aetiology. Importantly, it predicts the survival of patients with early disease (stages I and II), for whom classical clinical parameters provide limited information. The lack of predictive power in late disease stages III and IV emphasises that a protective immune microenvironment has to be established early in order to impact disease progression significantly. This signature includes the chemokine genes CXCL10, CCL5 and CCL2, whose expression correlates with markers of T helper 1 (Th1), CD8+ T and natural killer (NK) cells. Inflammatory cytokines (tumour necrosis factor α, interferon γ) and Toll-like receptor 3 ligands stimulate intratumoural production of these chemokines which drive tumour infiltration by T and NK cells, leading to enhanced cancer cell death.ConclusionA 14 immune-gene signature, which identifies molecular cues driving tumour infiltration by lymphocytes, accurately predicts survival of patients with HCC especially in early disease.

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

“…Thus, in patients with early-stage HCC, an immune gene signature associated with T-cell and NK-cell infiltration in resected HCC tissue was predictive of better survival (32). Toll-like receptor 3 expression that correlated with the degree of NK-cell infiltration was also a favorable predictor (33).…”

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

“…It has been demonstrated that tumor-infiltrating immune cells play an important role in host immune defense against tumor progression in various cancers. [8][9][10][11] These observations seem to provide a reasonable treatment direction and impel an increasing number of researchers to focus on immune responses in the tumor microenvironment.…”

“…8,17 Furthermore, NK cell-related genes are closely associated with NK cell function, and data from microarray experiments suggest that a series of NK cell-associated genes accurately predicts the clinical outcome of HCC patients, especially in early stages. 8 NK cells express a large number of immune recognition receptors (NKRs) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. One particular strategy that tumors have to escape the immune system is to target receptor-ligand systems to impair NK cytotoxicity.…”

Tumor-Associated Macrophages, Inflammation and Pathogenesis of Hepatocellular Carcinoma

“…Regulatory T cells, Kupffer cells (resident liver macrophages) and other TAMs impair cytotoxic T cell activities and their anticancer functions. Accordingly, several studies reported associations of decreased intratumoral densities of NK cells, low cytotoxic T, high TAM density and high regulatory T cell numbers with better pathological features and worse prognosis in HCC patients [19][20][21][22]. Recent studies have proven the importance of TAMs in HCC proliferation and survival [14,15,18,21,23,24].…”