Document Detail

Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review.
MedLine Citation:
PMID:  20927778     Owner:  NLM     Status:  MEDLINE    
The abundance of tumour-infiltrating T-cells has been associated with microsatellite instability (MSI) and a favourable prognosis in colorectal cancer. However, numerous molecular alterations have been associated with clinical outcome, and potentially confounding the biological and prognostic significance of tumour-infiltrating T-cells. We utilized a database of clinically and molecularly-annotated colon and rectal carcinoma cases (N = 768; stage I-IV) in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study) and quantified the densities of CD3(+), CD8(+), CD45RO(+) (PTPRC), and FOXP3(+) cells within neoplastic epithelial areas using an Ariol image analysis system and tissue microarray. We used Cox proportional hazard models to compute the mortality hazard ratio, adjusting for clinical and molecular features including KRAS, BRAF, and PIK3CA mutations, MSI, CIMP, and LINE-1 hypomethylation. The densities of CD8(+), CD45RO(+), and FOXP3(+) cells were significantly associated with patient survival in univariate analyses (P(trend) < 0.007). In the multivariate model, tumour-infiltrating CD45RO(+)-cell density, but not CD3(+), CD8(+) or FOXP3(+)-cell density, was significantly associated with survival (p = 0.0032). In multivariate linear regression analysis, MSI-high (p < 0.0001) and high-level tumour LINE-1 methylation (p = 0.0013) were independently associated with higher CD45RO(+)-cell density. The survival benefit associated with CD45RO(+) cells was independent of MSI and LINE-1 status. In conclusion, tumour-infiltrating CD45RO(+)-cell density is a prognostic biomarker associated with longer survival of colorectal cancer patients, independent of clinical, pathological, and molecular features. In addition, MSI-high and tumour LINE-1 methylation level are independent predictors of CD45RO(+)-cell density. Our data offer a possible mechanism by which MSI confers an improved clinical outcome and support efforts to augment the host immune response in the tumour microenvironment as a strategy of targeted immunotherapy.
Katsuhiko Nosho; Yoshifumi Baba; Noriko Tanaka; Kaori Shima; Marika Hayashi; Jeffrey A Meyerhardt; Edward Giovannucci; Glenn Dranoff; Charles S Fuchs; Shuji Ogino
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  The Journal of pathology     Volume:  222     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-10-26     Completed Date:  2011-01-03     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  350-66     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MeSH Terms
Antigens, CD45 / analysis
Colorectal Neoplasms / genetics,  immunology*
DNA Methylation
DNA, Neoplasm / genetics
Epidemiologic Methods
Long Interspersed Nucleotide Elements / genetics
Lymphocyte Count
Lymphocytes, Tumor-Infiltrating / immunology*
Microsatellite Instability
Middle Aged
Oligonucleotide Array Sequence Analysis
T-Lymphocyte Subsets / immunology*
Tumor Markers, Biological / analysis
Grant Support
K07 CA122826/CA/NCI NIH HHS; K07 CA122826/CA/NCI NIH HHS; K07 CA122826-03/CA/NCI NIH HHS; K07 CA122826-03S1/CA/NCI NIH HHS; P01 CA055075/CA/NCI NIH HHS; P01 CA055075-13/CA/NCI NIH HHS; P01 CA087969/CA/NCI NIH HHS; P01 CA087969-10/CA/NCI NIH HHS; P01 CA55075/CA/NCI NIH HHS; P01 CA87969/CA/NCI NIH HHS; P50 CA127003/CA/NCI NIH HHS; P50 CA127003/CA/NCI NIH HHS; P50 CA127003-03/CA/NCI NIH HHS; R01 CA151993/CA/NCI NIH HHS; R01 CA151993/CA/NCI NIH HHS; R01 CA151993-01/CA/NCI NIH HHS
Reg. No./Substance:
0/DNA, Neoplasm; 0/Tumor Markers, Biological; EC, CD45
Comment In:
J Pathol. 2011 Dec;225(4):628; author reply 629-30   [PMID:  21826670 ]

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