Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Oct;12(10):1383-97.
doi: 10.1517/14712598.2012.707184. Epub 2012 Jul 31.

Induced and natural regulatory T cells in human cancer

Theresa L Whiteside  1 , Patrick Schuler, Bastian Schilling
Affiliations
Review

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.

PubMed Disclaimer

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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mougiakakos D, Choudhury A, Lladser A, et al. Regulatory T cells in cancer. Adv Cancer Res. 2010;107:57–117. - PubMed
    1. Allan SE, Broady R, Gregori S, et al. CD4+ T-regulatory cells: toward therapy for human diseases. Immunol Rev. 2008;223:391–421. - PubMed
    1. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–64. - PubMed
    1. Bettini M, Vignali D. Regulatory T cells and inhibitory cytokines in autoimmunity. Curr Opin Immunol. 2009;21:612–18. - PMC - PubMed
    1. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67. - PubMed

Publication types