It was reported an analysis of T cell infiltrates in large cohorts of stage II and III CRC patients [
20]. Similar to our findings, they confirmed a low density of CD45RO + cells in patients with early signs of metastasis. They found also that CD45RO + and CD8+ T cells correlate with microsatellite instability in the tumor. High densities of intratumoral CD45RO+, CD8+, and strikingly FoxP3+ cells correlate with a good prognosis.
The question of the prognostic value of regulatory T cells in human cancers appears indeed to be a complex issue. Curiel et al. [
21] reported that the presence of high density of CD3+ CD4+ CD25+ FoxP3+ cells in malignant ascites of ovarian carcinoma correlated with advanced tumor staging and reduced survival. Those results were confirmed in other solid tumors, such as pancreatic ductal adenocarcinoma [
22] or hepatocarcinoma [
23]. Those findings gained a large interest since they supported the appealing hypothesis that the induction of Treg could be a major escape mechanism for human tumors. In this light, Treg could represent not only a prognostic marker but, even more importantly, a target for immunotherapy.
However, in follicular lymphoma and Hodgkin's lymphoma [
24,
25] high density of intratumoral Treg was shown to correlate with good prognosis. FoxP3+ T cell infiltration in head and neck cancer was associated with a better loco-regional control of the tumor. Multivariate analysis showed that the significant prognostic factors related to loco-regional control were the T stage and the intratumoral Treg infiltration [
26]. In CRC, high densities of FoxP3+ T cells were associated with microsatellite instability [
27,
28], feature usually associated with favorable prognosis. We found no association between the expression of FoxP3, CTLA4, GITR, IL10, and TGFb and the presence of lymph node or distant metastasis. In ovarian carcinoma, the absolute number of FoxP3+ lymphocytes infiltrating the tumor epithelium was an independent prognostic factor for longer DSS in advanced stage and metastatic patients [
29]. The issue is therefore still open and needs more precise analysis of the relative proportion of Treg versus helper and cytotoxic T cells, their spatial distribution in tumor, invaded lymph nodes and blood, of CD4 or CD8 FoxP3+ subpopulations [
30], as well as their functionality [
31]. Even more, the T cell plasticity where Treg can lose FoxP3 expression and change their phenotype [
32], and reversely, FoxP3-T cells can acquire FoxP3, without becoming regulatory [
33], adds complexity to these analysis.