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Previous Volume 353:2654-2666 December 22, 2005 Number 25 Next

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ABSTRACT

Background The role of tumor-infiltrating immune cells in the early metastatic invasion of colorectal cancer is unknown.

Methods We studied pathological signs of early metastatic invasion (venous emboli and lymphatic and perineural invasion) in 959 specimens of resected colorectal cancer. The local immune response within the tumor was studied by flow cytometry (39 tumors), low-density-array real-time polymerase-chain-reaction assay (75 tumors), and tissue microarrays (415 tumors).

Results Univariate analysis showed significant differences in disease-free and overall survival according to the presence or absence of histologic signs of early metastatic invasion (P<0.001). Multivariate Cox analysis showed that an early conventional pathological tumor–node–metastasis stage (P<0.001) and the absence of early metastatic invasion (P=0.04) were independently associated with increased survival. As compared with tumors with signs of early metastatic invasion, tumors without such signs had increased infiltrates of immune cells and increased levels of messenger RNA (mRNA) for products of type 1 helper effector T cells (CD8, T-BET [T-box transcription factor 21], interferon regulatory factor 1, interferon-, granulysin, and granzyme B) but not increased levels of inflammatory mediators or immunosuppressive molecules. The two types of tumors had significant differences in the levels of expression of 65 combinations of T-cell markers, and hierarchical clustering showed that markers of T-cell migration, activation, and differentiation were increased in tumors without signs of early metastatic invasion. The latter type of tumors also had increased numbers of CD8+ T cells, ranging from early memory (CD45RO+CCR7–CD28+CD27+) to effector memory (CD45RO+CCR7–CD28–CD27–) T cells. The presence of high levels of infiltrating memory CD45RO+ cells, evaluated immunohistochemically, correlated with the absence of signs of early metastatic invasion, a less advanced pathological stage, and increased survival.

Conclusions Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival.

Source Information

From INSERM Unité 255, René Descartes Faculté de Médecine, Assistance Publique–Hôpitaux de Paris, Cordeliers Biomedical Research Center, University Paris 6, Paris (F.P., M.C., A.C., A.K., M.N., W.-H.F., J.G.); the Laboratory of Immunology (F.P., W.-H.F.) and the Departments of General and Digestive Surgery (A.B., P.-H.C.) and Pathology (D.D., T.M., P.B.), Georges Pompidou European Hospital, Paris; and the Institute for Genomics and Bioinformatics, Graz University of Technology, Graz, Austria (F.S.-C., R.M., B.M., Z.T.).

Drs. Pagès and Berger contributed equally to the article.

Address reprint requests to Dr. Galon at INSERM U255, 15 rue de l'Ecole de Médecine, Centre de Recherches Biomédicales des Cordeliers, 75006 Paris, France, or at jerome.galon{at}u255.bhdc.jussieu.fr.

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Related Letters:

Immune Cells in Colorectal Cancer
Wolf D., Marth C., Wolf A. M., Pagès F., Galon J.
Extract | Full Text | PDF  
N Engl J Med 2006; 354:1531-1532, Apr 6, 2006. Correspondence

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