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

ABSTRACT: OBJECTIVE: Hepatocellular 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. METHODS: Using 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. RESULTS: The 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 ?, interferon ?) 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. CONCLUSION: A 14 immune-gene signature, which identifies molecular cues driving tumour infiltration by lymphocytes, accurately predicts survival of patients with HCC especially in early disease.

SUBMITTER: Chew V

PROVIDER: S-EPMC3273680 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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

Chew Valerie V Chen Jinmiao J Lee Deming D Loh Evelyn E Lee Joyce J Lim Kiat Hon KH Weber Achim A Slankamenac Ksenija K Poon Ronnie T P RT Yang Henry H Ooi London Lucien P J LL Toh Han Chong HC Heikenwalder Mathias M Ng Irene O L IO Nardin Alessandra A Abastado Jean-Pierre JP

Gut 20110919 3

<h4>Objective</h4>Hepatocellular 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.<h4>Methods</h4>Using quantitative PCR, the ...[more]

PMID: 21930732

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Project description:BACKGROUND:Colorectal cancer (CRC) is the second leading cancer killer in the US today and patients with metastatic disease have only a 14% 5-year survival. One of the most impactful recent advances in cancer therapy, immune checkpoint inhibition, has not been shown to be effective for the majority of these patients. In this study, we use The Cancer Genome Atlas (TCGA) and recently developed informatic-based tools to identify targets for immune based therapy in colorectal cancer patients. METHODS:Open access, pre-processed (level 3) mRNA data and clinical data from colorectal patients from the TCGA was downloaded from FireCloud. Using the Microenvironment Cell Populations-Counter method (MCP-Counter), cytotoxic lymphocyte scores were calculated for all patients. Patients were then grouped by cytotoxic lymphocyte score (High vs Low), pathologic stage, and location to identify differentially expressed genes. Pathway enrichment analysis was performed using Reactome to determine differentially expressed genes associated with immune pathways. Survival analysis was performed with identified differentially expressed genes. RESULTS:In the TCGA dataset, there are 461 colon and 172 rectal cancer patients. After stratifying patients by cytotoxic lymphocyte score, anatomical location, and stage, we found a significant number of differentially expressed genes. We identified one pathway, "immunoregulatory interactions between a lymphoid and non-lymphoid cell", that was highly enriched and included in all tumor locations and stages. Survival analysis performed with differentially expressed genes in this pathway identified 21 different genes associated with survival and cytotoxic lymphocyte infiltration, with ~?70% of these genes occurring in the metastatic right-sided CRC group. Specifically, all genes associated with survival in the metastatic right-sided colorectal cancer group with low cytotoxic lymphocyte scores positively impacted survival. CONCLUSIONS:Utilizing the TCGA, a publicly available dataset, and informatics-based analyses, we identified potential targets to improve immune based therapy in colorectal cancer. Additionally, we note the most targets in metastatic right-sided CRC patients, the patient group with the worst predicted survival. The results from this study demonstrate the ability of informatics-based analytic techniques to identify new therapeutic targets as well as improve patient selection for intervention, helping us to achieve the goals of precision-based oncology.

Dataset Information

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

Publications

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

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