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Fas ligand and tumour counter‐attack in colorectal cancer stratified according to microsatellite instability status
Author(s) -
MichaelRobinson Julie M,
Pandeya Nirmala,
Cummings Margaret C,
Walsh Michael D,
Young Joanne P,
Leggett Barbara A,
Purdie David M,
Jass Jeremy R,
RadfordSmith Graham L
Publication year - 2003
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1406
Subject(s) - microsatellite instability , fas ligand , colorectal cancer , tumor infiltrating lymphocytes , immunohistochemistry , cancer research , cancer , biology , adenocarcinoma , pathology , apoptosis , oncology , medicine , microsatellite , immunotherapy , gene , programmed cell death , genetics , allele
Expression of membrane‐bound Fas ligand (FasL) by colorectal cancer cells may allow the development of an immune‐privileged site by eliminating incoming tumour‐infiltrating lymphocytes (TILs) in a Fas‐mediated counter‐attack. Sporadic colorectal cancer can be subdivided into three groups based on the level of DNA microsatellite instability (MSI). High‐level MSI (MSI‐High) is characterized by the presence of TILs and a favourable prognosis, while microsatellite‐stable (MSS) cancers are TIL‐deficient and low‐level MSI (MSI‐Low) is associated with an intermediate TIL density. The purpose of this study was to establish the relationship between MSI status and FasL expression in primary colorectal adenocarcinoma. Using immunohistochemistry and a selected series of 101 cancers previously classified as 31 MSI‐High, 30 MSI‐Low, and 40 MSS, the present study sought to confirm the hypothesis that increased TIL density in MSI‐High cancers is associated with low or absent membrane‐bound FasL expression, while increased FasL in MSS cancers allows the killing of host TILs. TUNEL/CD3 double staining was also used to determine whether MSS cancers contain higher numbers of apoptotic TILs in vivo than MSI‐High or MSI‐Low cancers. Contrary to the initial hypothesis, it was found that MSI‐High cancers were associated with higher FasL expression ( p = 0.04) and a stronger intensity of FasL staining ( p = 0.007). In addition, mucinous carcinomas were independently characterized by increased FasL expression ( p = 0.03) and staining intensity ( p = 0.0005). Higher FasL expression and staining intensity did not correlate with reduced TIL density or increased numbers of apoptotic TILs. However, consistent with the hypothesis that curtailment of the host anti‐tumour immune response contributes to the poor prognosis in MSS cancers, it was found that apoptotic TILs were most abundant in MSS carcinomas and metastatic Dukes' stage C or D tumours ( p = 0.004; p = 0.046 respectively). This study therefore suggests that MSS colorectal cancers are killing incoming TILs in an effective tumour counter‐attack, but apparently not via membrane‐bound FasL. Copyright © 2003 John Wiley & Sons, Ltd.