Effector memory T cells, early metastasis, and survival in colorectal cancer.
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-gamma, 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.
Pagès
Franck
F
INSERM Unité 255, René Descartes Faculté de Médecine, Assistance Publique-Hôpitaux de Paris, Cordeliers Biomedical Research Center, University Paris 6, Paris, France.
Berger
Anne
A
Camus
Matthieu
M
Sanchez-Cabo
Fatima
F
Costes
Anne
A
Molidor
Robert
R
Mlecnik
Bernhard
B
Kirilovsky
Amos
A
Nilsson
Malin
M
Damotte
Diane
D
Meatchi
Tchao
T
Bruneval
Patrick
P
Cugnenc
Paul-Henri
PH
Trajanoski
Zlatko
Z
Fridman
Wolf-Herman
WH
Galon
Jérôme
J
D000704:Analysis of Variance; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000556:secondary; D004617:Embolism / Q000209:etiology; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D017493:Leukocyte Common Antigens; D008207:Lymphatic Metastasis / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness / Q000276:immunology; D009362:Neoplasm Metastasis / Q000276:immunology*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D012333:RNA, Messenger / Q000096:biosynthesis; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
D012333:RNA, Messenger; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1