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Induced and natural regulatory T cells in human cancer - PubMed

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Induced and natural regulatory T cells in human cancer

Theresa L Whiteside et al. Expert Opin Biol Ther. 2012 Oct.

Abstract

Introduction: Evidence suggests that FOXP3(+)CD25(high)CD4(+) regulatory T cells (Treg) which accumulate in cancer may have beneficial or unfavorable effects on prognosis. The presence in tumor-associated inflammatory infiltrates of two subsets of Treg with distinct phenotypic and functional profiles might explain these conflicting observations.

Areas covered: Human inducible (i) Treg arising by tumor-driven conversion of conventional CD4(+) T cells are highly suppressive, therapy-resistant Treg which down-regulate anti-tumor immune responses, promoting tumor growth. Natural (n) Treg, normally responsible for maintaining peripheral tolerance, control cancer-associated inflammation, which favors tumor progression. This division of labor between nTreg and iTreg is not absolute, and overlap may be common. Nevertheless, iTreg play a critical and major role in cancer and cancer therapy. The tumor microenvironment determines the type, frequency and suppression levels of accumulating Treg.

Expert opinion: In cancer, a selective removal or silencing of iTreg and not of nTreg should be a therapeutic goal. However, the implementation of this challenging strategy requires further studies of cellular and molecular crosstalk among immune cells in the tumor microenvironment.

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Conflict of interest statement

Declaration of interest

Supported in part by the NIH grant PO1 CA109688 to TLW. P Schuler was supported by a grant from the Pittsburgh-Essen Partnership Program.

Figures

Figure 1
Figure 1. Inducible Treg (Tr1) generated in co-cultures with tumor cells

A. A schematic of the co-culture of purified CD4+CD25neg T cells with autologous immature dendritic cells (iDC), irradiated HNSCC cells and cytokines used for Tr1 generation. B. Phenotypic characteristics of human Tr1 cells generated in 10 day co-cultures and compared with conventional CD4+ T cells cultured in the presence of anti-CD3/anti-CD28 mAb and IL-2 for 10 days. Asterisks indicate significant (p < 0.01) differences in the % positive cells. The data are from 5 independent experiments. C. Functional properties (proliferation or IL-10 production) by T cells expanding in co-cultures over 10 days. The data were generated with T cells from one of the co-cultures described above.

Figure 2
Figure 2. Expression of CD73 on Tr1 cells generated in co-cultures of CD4+CD25neg T cells with irradiated tumor cells, autologous DC and cytokines as shown in Figure 1

Flow cytometry shows surface expression of CD73 on 40% of Tr1 cells (solid line). Isotype control is shown as a dotted line. Tr1 cells from another co-culture were also stained with anti-CD39 (FITC) and anti-73 (PE) antibodies and examined for co-expression of the two ectonucleotidases in a wet mount by fluorescence microscopy. In A, DAPI control; B, CD39+ cells; C, CD73+ cells; D. merged view with a yellow color identifying Tr1 cells co-expressing CD39 and CD73. Original mag × 400. Courtesy of Drs. M. Mandapathil (flow cytometry) and M. Harasymczuk (fluorescence microscopy).

Figure 3
Figure 3. The presence of Tr1-like cells at tumor sites and in the peripheral circulation of patients with cancer

A. Expression of CD4+ T cells co-expressing CD132 and TGF-β infiltrating human HNSCC. A frozen tumor section stained with mAbs to CD4; CD132 and TGF-β and examined in a fluorescence microscope. Mag × 600. B. Flow cytometry data (reproduced with permission from ref. by Bergmann et al.) for expression of CD132, TGF-β, IL-10 and IL-4 in CD3+CD4+ lymphocytes in PBMC or TIL of a representative HNSCC patient.

Figure 4
Figure 4

Schematic overview of human nTreg and iTreg emphasizing their distinct phenotypes and functional attributes in respect to adenosine signaling and adenosine production.

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