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Review
. 2011 Jul;60(7):909-18.
doi: 10.1007/s00262-011-1046-y. Epub 2011 Jun 5.

Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer

Sylvain Ladoire  1 , François Martin, François Ghiringhelli
Affiliations
Review

Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer

Sylvain Ladoire et al. Cancer Immunol Immunother. 2011 Jul.

Abstract

The accumulation of regulatory T cells (Tregs) at high density in various human carcinomas is generally associated with a poor prognosis, as expected from their capacity to inhibit antitumor immunity. Surprisingly, in patients bearing colorectal carcinoma (CRC), high regulatory T-cell infiltration is associated with a favorable prognosis, as shown by the analysis of seven clinical studies. To explain this paradox, we emphasize a putative role of the dense microbiological flora present in the large intestine with a trend toward translocation through the tumor. This microbiological hazard requires a T-cell-mediated inflammatory anti-microbial response that involves Th17 cells and can thereby promote cancer growth. This Th17-cell-dependent proinflammatory and tumor-enhancing response can be attenuated by Tregs, thus constituting a possible explanation for their favorable role in CRC prognosis. The link between a high density of FOXP3-positive cells in CRC immune infiltrates and favorable prognosis should lead us to consider tumor infiltrating Tregs as allies to be respected, rather than enemies to be destroyed during trials of CRC treatment.

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Figures

Fig. 1
Fig. 1
Opposite prognostic effect of Foxp3+ Treg cells according to the tumor type: In tumors growing in a non-infected microenvironment like breast carcinoma (a), tumor cells promote Treg accumulation notably through TGF-β secretion, which blunts Th1-dependent antitumor immune response, which normally involves secretion of IL-12 by dendritic cells, and secretion of INF-γ, perforines and GzB by T cells and NK cells. Conversely, in tumors growing in a septic environment, like CRC (b), bacterial translocation across the mucosal surface due to increased permeability of tight junctions and/or ulceration of the tumor triggers the production of proinflammatory cytokines by dendritic cells. This inflammatory anti-microbial response notably involves Th17 cells, which can stimulate angiogenesis through VEGF production and induce inflammatory reaction triggered by cytokines like IL-17, IL-1, IL-6, and TNF-α, thus contributing to tumor promotion. This proinflammatory and tumor-enhancing response could be attenuated by Tregs, thus constituting a possible explanation for their favorable role in CRC prognosis TGF-β transforming growth factor-β, NK natural killer cells, Th1 T helper type 1 cells, INF-γ interferon γ, GzB granzyme B, VEGF vascular endothelial growth factor, TLR toll-like receptor, NLR nod-like receptor, TNF-α tumor necrosis factor α
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