title: Fas ligand and tumour counter-attack in colorectal cancer stratified according to microsatellite instability status.
abstract: 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.
authors.affiliation: Inflammatory Bowel Disease Laboratory, Royal Brisbane Hospital Foundation Clinical Research Centre, Brisbane, Australia.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Michael-Robinson
authors.forename: Nirmala
authors.initials: N
authors.lastname: Pandeya
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Cummings
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leggett
authors.forename: David M
authors.initials: DM
authors.lastname: Purdie
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
authors.forename: Graham L
authors.initials: GL
authors.lastname: Radford-Smith
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D000368:Aged; D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008024:Ligands; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D018895:Microsatellite Repeats; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins