Biomolecular Network Reconstruction Identifies T-Cell Homing Factors Associated With Survival in Colorectal Cancer

doi:10.1053/j.gastro.2009.10.057

Gastroenterology

Volume 138, Issue 4, April 2010, Pages 1429-1440

https://doi.org/10.1053/j.gastro.2009.10.057 Get rights and content

Background & Aims

Colorectal cancer is a complex disease involving immune defense mechanisms within the tumor. Herein, we used data integration and biomolecular network reconstruction to generate hypotheses about the mechanisms underlying immune responses in colorectal cancer that are relevant to tumor recurrence.

Methods

Mechanistic hypotheses were formulated on the basis of data from 108 patients and tested using different assays (gene expression, phenome mapping, tissue-microarrays, T-cell receptor [TCR] repertoire).

Results

This integrative approach revealed that chemoattraction and adhesion play important roles in determining the density of intratumoral immune cells. The presence of specific chemokines (CX3CL1, CXCL10, CXCL9) and adhesion molecules (ICAM1, VCAM1, MADCAM1) correlated with different subsets of immune cells and with high densities of T-cell subpopulations within specific tumor regions. High expression of these molecules correlated with prolonged disease-free survival. Moreover, the expression of certain chemokines associated with particular TCR repertoire and specific TCR use predicted patient survival.

Conclusions

Data integration and biomolecular network reconstruction is a powerful approach to uncover molecular mechanisms. This study shows the utility of this approach for the investigation of malignant tumors and other diseases. In colorectal cancer, the expression of specific chemokines and adhesion molecules were found as being critical for high densities of T-cell subsets within the tumor and associated with particular TCR repertoire. Intratumoral-specific TCR use correlated with the prognosis of the patients.

Section snippets

Patients and Database

The records of CRC patients who underwent a primary resection of their tumor at the Laennec George Pompidou European Hospital (HEGP) Hospitals between 1996 and 2004 were reviewed and described previously.¹⁸ Histopathologic and clinical findings were scored according to the International Union Against Cancer (UICC)-TNM staging system. For details, see the Supplementary Materials and Methods section and Supplementary Table 1. A secure web-based database Tumor Microenvironment Database (TME.db)

Immune-Related Genes Are Associated With the Absence of Tumor Recurrence

We first investigated gene expression in colorectal tumors. We determined the median cut-off values for each gene, and performed survival analysis for up to 10 years after primary tumor resection. Log-rank P values associated with disease-free survival then were calculated and hazard ratios were illustrated by the size of each node in a network (Figure 1). The expression of genes associated with tumor invasion (CEACAM1, CD97), metastasis spreading (ACE, EBAG9, MMP7), tumor anti-apoptotic

Discussion

The staggering complexity of multifactorial diseases such as cancer poses significant challenges for the development of stratified or personalized therapies. The integrated analysis of diverse datasets might circumvent these challenges and provide an enhanced understanding of complex systems, such as the tumor microenvironment. We applied such an integrated approach and performed global analyses of the phenome (large-scale flow cytometry experiments), transcriptome, tissue microarrays of

Acknowledgments

The authors are grateful to Dr Ion Gresser and Dr John Nelson for providing helpful comments and critical review of the manuscript.

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: Conflicts of interest The authors disclose no conflicts.

: Funding This work was supported by grants from the Association pour la Recherche sur le Cancer, the National Cancer Institute, the Canceropole Ile de France, Ville de Paris, INSERM, the Austrian Federal Ministry of Science and Research (Genome Programme Austria [GEN-AU] project Bioinformatics Integration Network), the Austrian Science Fund (SpezialForschungBereich [SFB] project Lipotoxicity), and the European Commission (Seventh Framework Programme [7FP], Geninca Consortium, grant number 202230).

View full text

Basic—Alimentary TractBiomolecular Network Reconstruction Identifies T-Cell Homing Factors Associated With Survival in Colorectal Cancer

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients and Database

Immune-Related Genes Are Associated With the Absence of Tumor Recurrence

Discussion

Acknowledgments

Cell

Cell

Cell

Cell

Cell

A plaidoyer for “systems immunology”

Immunol Rev

Systems biologyLife's complexity pyramid

Science

The immunogenicity of colorectal cancers with high-degree microsatellite instability

World J Surg Oncol

Human tumor antigens, immunosurveillance, and cancer vaccines

Immunol Res

Cancer immunology

N Engl J Med

Inflammation and cancer

Nature

The three Es of cancer immunoediting

Annu Rev Immunol

IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity

Nature

Differential tumor surveillance by natural killer (NK) and NKT cells

J Exp Med

Adaptive immunity maintains occult cancer in an equilibrium state

Nature

Basic—Alimentary Tract
Biomolecular Network Reconstruction Identifies T-Cell Homing Factors Associated With Survival in Colorectal Cancer