title: The "Fas counterattack" is not an active mode of tumor immune evasion in colorectal cancer with high-level microsatellite instability.
abstract: Microsatellite instability (MSI) is an alternative pathway of colorectal carcinogenesis. It is found in 10% to 15% of sporadic colorectal neoplasms and is characterized by failure of the DNA mismatch-repair system. High-level MSI (MSI-H) is associated with tumor-infiltrating lymphocytes (TILs) and a favorable prognosis. Expression of Fas ligand (FasL/CD95L) by cancer cells may mediate tumor immune privilege by inducing apoptosis of antitumor immune cells. The aim of this study was to investigate the relationship between FasL expression and MSI status in primary colon tumors. Using immunohistochemistry, we detected FasL expression in 91 colorectal carcinoma specimens, previously classified according to the level of MSI as MSI-H (n = 26), MSI-low (MSI-L) (n = 29), and microsatellite stable (n = 36). Tumor-infiltrating lymphocyte density was quantified by immunohistochemical staining for CD3. MSI-H tumors were significantly associated with reduced frequency (P = .04) and intensity (P = .066) of FasL expression relative to non-MSI-H (ie, microsatellite stable and MSI-L) tumors. Higher FasL staining intensity correlated with reduced TIL density (P = .059). Together, these findings suggest that the abundance of TILs found in MSI-H tumors may be due to the failure of these tumor cells to up-regulate FasL and may explain, in part, the improved prognosis associated with these tumors.
authors.affiliation: Department of Medicine, National University of Ireland Cork, Clinical Science Building, Cork University Hospital, Wilton, Cork, Ireland. a.houston@ucc.ie
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Houston
authors.forename: Julie M
authors.initials: JM
authors.lastname: Michael-Robinson
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Cummings
authors.forename: Aideen E
authors.initials: AE
authors.lastname: Ryan
authors.forename: Douglas
authors.initials: D
authors.lastname: Lincoln
authors.forename: Nirmala
authors.initials: N
authors.lastname: Pandeya
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
authors.forename: Graham L
authors.initials: GL
authors.lastname: Radford-Smith
authors.forename: Joe
authors.initials: J
authors.lastname: O'Connell
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D017252:CD3 Complex / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053222:Fas Ligand Protein / Q000378:metabolism*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007108:Immune Tolerance; D007124:Immunoenzyme Techniques; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D008297:Male; D053842:Microsatellite Instability
chemical_list: D017252:CD3 Complex; C505661:FASLG protein, human; D053222:Fas Ligand Protein