Thursday, April 28, 2016

Making sense of Foxp3 as a prognostic value in tumors

A transcription factor Foxp3 controls functionality of T cell subset called regulatory T cells (Tregs). Seminal studies in mice clearly showed that Foxp3+ T cells play a dominant role in suppressing excessive immune response.

But human studies introduced an additional confusion in Tregs field. Unlike, mouse Foxp3, human Foxp3 is up-regulated in human naive CD4 T cells upon activation. In fact, human Foxp3+ T cell population is divided into Foxp3low and Foxp3high population. Foxp3low population lack regulatory properties, whereas Foxp3high population represents a bona fide Tregs cells.

However, such separation of Foxp3 marker within individual tumor clinical samples are not always possible and ordinarily cancer biopsies are grouped into Foxp3hi or Foxp3lo for Foxp3 mRNA total expression levels that are above or below the [arbitrary] median. So, it is not surprising that [total] expression level Foxp3 biomarker in tumor tissue does not correlate with overall survival.

In this regard, it is interesting to read a new paper in Nature Medicine showing that inclusion of two additional biomarkers, IL-12 and TGFβ1, could provide that differentiating power to transform Foxp3 expression into a prognostic factor in cancer diagnostics.

For this study the authors analyzed colorectal cancer samples. They found that cancer samples could be grouped into A and B types based on presence of two separate Foxp3+ T cell population: Foxp3low and Foxp3high population. Type A samples mostly have Foxp3high population whereas type B samples have both Foxp3low and Foxp3high populations.

As expected Foxp3low T cell population lacked suppressive [cell proliferation inhibition] quality and most likely represent conventional activated T cells.

Gene expression analysis of type A and B cancer tissue showed that type B were enriched with several cytokines such as IL-12, TNF-α and also TGFβ1. In vitro Foxp3 conversion assay showed that when combined with TGFβ1, interleukin-12 [but not TNF-α] could specifically increase naive T cell differentiation into Foxp3low population (most likely by preventing their differentiation into Foxp3high population).

Interestingly, when cancer samples were classified based on mRNA expression levels of Foxp3, IL-12 and TGFβ1, there were clear differences in patients survival between groups:

(1) as expected Foxp3 expression by itself had no prognostic value

(2) in samples with IL-12loTGFβ1lo expression, mRNA Foxp3hi was associated with poor prognosis

and (3) unexpectedly, in samples with IL-12hiTGFβ1hi expression, mRNA Foxp3hi was associated with a better prognosis.

Finally, the authors find that cancer samples with IL-12hiTGFβ1hi expression harbored more of gut microbe Fusobacterium nucleatum.

In summary, this study indicates following scenario:

(a) in colorectal cancers, detection of mRNA Foxp3 by itself has no prognostic value.
(b) however, cancer biopsies with Foxp3hiIL-12loTGFβ1lo mRNA expression could mean poor prognosis, because such samples contain mostly bona fide Tregs cells.
(c) but, cancer biopsies with Foxp3lo/hiIL-12hiTGFβ1hi mRNA expression could mean good prognosis, because such samples contain mostly Foxp3low population or it has sufficient inflammatory milieu to override any suppression by bona fide Tregs cells.

David Usharauli

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