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.

Pathology Features in Bethesda Guidelines Predict Colorectal Cancer Microsatellite Instability: A Population-Based Study

“…30,31 Alternatively, MSI-H colorectal cancers may fail to elaborate Fas ligand implicated in the counterattack by malignant cells on contact with lymphoid cells. 32 Loss of CDX2 expression has been linked with poor differentiation and particularly with the undifferentiated variant described as medullary carcinoma. 33 Only one medullary carcinoma was diagnosed in this study, but it is likely that examples with focal glandular differentiation would have been included in the poorly differentiated subset.…”

Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer

“…Review of the literature shows a wide variability in methodology used in counting TILs [20, 54,55] which is then reflected in different averages in numbers of TILs per high power field in MSI-H cancers. Smryk et al…”

High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability

“…For example, immune evasion mechanisms such as impairment or loss of the human leukocyte antigen class I-mediated antigen presentation (Bicknell et al, 1996;Cabrera et al, 2003;Kloor et al, 2005) or the expression of Fas ligand (Okada et al, 2000;Michael-Robinson et al, 2003) are frequent in MSI-H CRCs.…”