title: Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: INSERM, Integrative Cancer Immunology Team, INSERM U872, Paris, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mlecnik
authors.forename: Marie
authors.initials: M
authors.lastname: Tosolini
authors.forename: Pornpimol
authors.initials: P
authors.lastname: Charoentong
authors.forename: Amos
authors.initials: A
authors.lastname: Kirilovsky
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bindea
authors.forename: Anne
authors.initials: A
authors.lastname: Berger
authors.forename: Matthieu
authors.initials: M
authors.lastname: Camus
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gillard
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Wolf-Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Franck
authors.initials: F
authors.lastname: Pagès
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Trajanoski
authors.forename: Jérôme
authors.initials: J
authors.lastname: Galon
mesh_terms: D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology; D018925:Chemokines / Q000235:genetics / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality*; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D006801:Humans; D010641:Phenotype; D011379:Prognosis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D046888:Tissue Array Analysis
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D011948:Receptors, Antigen, T-Cell