Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer.
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.
Mlecnik
Bernhard
B
INSERM, Integrative Cancer Immunology Team, INSERM U872, Paris, France.
Tosolini
Marie
M
Charoentong
Pornpimol
P
Kirilovsky
Amos
A
Bindea
Gabriela
G
Berger
Anne
A
Camus
Matthieu
M
Gillard
Mélanie
M
Bruneval
Patrick
P
Fridman
Wolf-Herman
WH
Pagès
Franck
F
Trajanoski
Zlatko
Z
Galon
Jérôme
J
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
D015815:Cell Adhesion Molecules; D018925:Chemokines; D011948:Receptors, Antigen, T-Cell