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

Abstract

High-level microsatellite instability (MSI-H) in colorectal cancer accounts for about 12% of colorectal cancers and is typically associated with a dense infiltration with cytotoxic CD8-positive lymphocytes. The role of regulatory T cells that may interfere with the host's antitumoural immune response in MSI-H colorectal cancers has not been analysed yet. Using an antibody directed against the regulatory T-cell marker transcription factor forkhead box P3 (FOXP3), regulatory T cells were examined in 70 colorectal cancers with known MSI status (MSI-H, n ¼ 37; microsatellite stable, n ¼ 33). In MSI-H colorectal cancers, we found a significantly higher intraepithelial infiltration with FOXP3-positive cells (median: 8.5 cells per 0.25 mm 2 vs 3.1 cells per 0.25 mm 2 in microsatellite stable, Po0.001), and a significantly elevated ratio of intraepithelial to stromal infiltration (0.05 vs 0.01 in microsatellite stable, Po0.001). CD8-positive cell counts were related positively to the number of FOXP3-positive cells (Spearman's r ¼ 0.56 and 0.55, respectively). Our results show that the elevated number of CD8-positive lymphocytes found in MSI-H colorectal cancers is paralleled by an enhanced infiltration with CD8-negative FOXP3-positive cells. These data suggest that FOXP3-positive cells may play a role in the regulation of the immune response directed against MSI-H colorectal cancers at the primary tumour site.

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

“…In contrast, Michel et al [92] were the first to show that the density of FOXP3 + Treg cells infiltrating CRC were significantly higher in MSI-H tumors using immunohistochemistry, paralleling the enhanced number of CD8 + cells in these tumors. In addition, Sinicrope et al [96] showed that the intraepithelial to stromal ratios for FOXP3 + and CD3 + T cells were increased in MMR-deficient versus MMR-proficient colon cancers, yet the CD3 + /FOXP3 + ratio were similar in both groups and the prognostic impact of this ratio was maintained in the full study cohort.…”

Immune infiltration in human tumors: a prognostic factor that should not be ignored

“…The impact of lymphoid islets with germinal center-like architecture found in the vicinity of the tumors is debated and will be discussed below. Most authors considered the immune infiltrate as reflecting tumor cell modifications such as MSI (Popat et al, 2005;Le Gouvello et al, 2008;Michel et al, 2008), altered expression of major histocompatibility complex class I molecules (Bicknell et al, 1996) or production of chemokines (Balkwill, 2004) rather than representing a phenomenon that may control tumor dissemination. Immune infiltration was thus considered as an additional, rather weak, prognostic factor with no major impact on classical tumor, associated features, such as size (T), lymph node (N) or metastatic (M) invasion, oncogene mutation or VEGF production.…”

“…Indeed, multivariate analysis showed that the only significant prognostic factors related to locoregional control were T stage and T reg infiltration of the tumor (Badoual et al, 2006). In colorectal cancer, high densities of FoxP3 T cells were associated with MSI (Le Gouvello et al, 2008;Michel et al, 2008), a feature usually associated with favorable prognosis. We found no association between FoxP3, CTLA-4, GITR, IL-10, TGF-b and the presence of intratumoral or distant metastasis.…”

Colorectal Cancer: Sailing with a T-Cell EMAST

“…Further support for this argument comes from the fact that when T-regulatory cells were assessed by staining for the transcription factor, forkhead box P3 (FOXP3), this subtype of CD4? T cells was significantly increased in MSI tumors [19]. These findings underscore the importance of identification of individual subtypes of CD4?…”

“…T cells, CD4? T-cell populations consist of several subtypes, such as T helper type 1 (Th1), Th2, Th17 and other T-regulatory cells [19]. In view of this, for future studies it may be worth expanding the scope of IHC staining to include markers that represent these specific T-cell subtypes.…”