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PMID: 24022192 Published · ppublish English Journal Article

The in situ local immune response, tumour senescence and proliferation in colorectal cancer.

British journal of cancer ·Vol. 109 ·No. 8 ·2013-10-15 ·Pages 2207-16

Roxburgh CS, Richards CH, Macdonald AI, Powell AG, McGlynn LM, McMillan DC, Horgan PG, Edwards J, Shiels PG

Abstract

Immune cell infiltrates are important determinants of colorectal cancer (CRC) outcome. Their presence may be driven by tumour or host-specific factors. From previous studies in mice, senescence, a state of cell cycle arrest, may moderate tumour progression through upregulation of antitumour immune responses. The relationships between senescence and immune infiltrates have not previously been studied in humans. We explore whether a marker of senescence (p16(ink4a)) in combination with low level expression of a proliferation marker (ki-67) relate to T cell infiltrates in CRC, and whether p16(ink4a), Ki-67 and immune infiltrates have similar prognostic value. Immunostaining of p16(inka) and Ki-67 was performed within a CRC tissue microarray. Nuclear p16(inka) and Ki-67 were categorised as high/low. T-cell markers, CD3, CD45RO, CD8 and FOXP3 were scored separately as high/low grade in three areas of the tumour: the invasive margin (IM), tumour stroma and cancer cell nests (CCNs). results: Two hundred and thirty stage I-III cancers were studied. High nuclear p16(ink4a) was expressed in 63% and high proliferation (Ki-67 >15%) in 61%. p16(ink4a) expression was associated with reduced CD45RO+ cells at the IM (P<0.05) and within the stroma (P<0.05) and reduced CD8+ cells at the IM (P<0.01). A low Ki-67 proliferative index was associated with reduced density of CD3+ cells in CCNs (P<0.01), reduced CD45RO+ cells at the IM (P<0.05) and within the CCNs (P<0.001), reduced FOXP3+ cells at the IM (P<0.001), within the stroma (P=0.001) and within CCNs (P<0.001) and reduced CD8+ cells at the IM (P<0.05) and within the CCNs (P<0.05). Tumours with both a low proliferative index and expression of p16(ink4a) demonstrated similar consistent relationships with reduced densities of T-cell infiltrates. On multivariate analysis, TNM stage (P<0.001), low CD3 cells at the IM (P=0.014), low CD8 cells at the IM (P=0.037), low proliferation (Ki-67; P=0.013) and low senescence (p16(ink4a); P=0.002) were independently associated with poorer cancer survival. Senescence, proliferation and immune cell infiltrates are independent prognostic factors in CRC. Although related to survival, p16(ink4a)-associated senescence is not associated with an upregulation of antitumour T-cell responses.

MeSH Terms
Aged Cell Growth Processes/immunology Cellular Senescence/immunology Colorectal Neoplasms/immunology,pathology Cyclin-Dependent Kinase Inhibitor p16 Female Humans Immunohistochemistry Ki-67 Antigen/biosynthesis,immunology Lymphocytes, Tumor-Infiltrating/immunology Male Middle Aged Neoplasm Proteins/biosynthesis,immunology Neoplasm Staging Paraffin Embedding T-Lymphocytes/immunology Tissue Array Analysis
Chemicals
CDKN2A protein, human Cyclin-Dependent Kinase Inhibitor p16 Ki-67 Antigen Neoplasm Proteins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Roxburgh C S
Academic Unit of Surgery, Royal Infirmary, University of Glasgow, Glasgow, UK.
Richards C H
Macdonald A I
Powell A G
McGlynn L M
McMillan D C
Horgan P G
Edwards J
Shiels P G
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Article Info
Journal
British journal of cancer
Abbr.
Br J Cancer
ISSN
1532-1827
DOI
10.1038/bjc.2013.556
Published
2013-10-15
Epub
2013-00-10
Pages
2207-16
Language
English
Region
England
NLM ID
0370635
PMCID
PMC3798960
Subset
IM
External Links
PubMed source DOI: 10.1038/bjc.2013.556 PMC Full Text View journal details
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