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.
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.
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.
"+ T-cell subsets after subimmunogenic stimulation, e.g. in the presence of immunosuppressive cytokines as IL-10 or TGF-β and therefore were termed inducible Tregs (iTregs) (Mills, 2004). These iTregs are considered to be mainly responsible for a controlled decline of an immune response against pathogens (Povoleri et al., 2013) and suppress anti-tumour immune responses, thereby promoting tumour growth (Whiteside et al., 2012). Due to these different roles in the immune system much effort has been put into the phenotypical discrimination of iTregs and nTregs. "
"Acta (2014), http://dx.doi.org/10.1016/j.bbamcr.2014.10.024 forkhead box protein 3 (FoxP3) expression in the highly suppressive, therapy-resistant inducible T regulatory cells (iTreg) , which promote tumor progression by down-regulating effector T cells . Evaluating the consequences of Orai1 and TRPC1 inhibition on the immune response against cancer development is, therefore, mandatory before introducing this approach into a pre-clinical setting. "
"In a variety of malignancies, increased frequencies of Tregs has been shown to correlate with a poor prognosis for patients, though this observation is not absolute (50). The profoundly suppressive tumor microenvironment has been shown to promote the generation of regulatory immune responses, using factors such as TGF-β or adenosine to mediate the conversion of effector lymphocytes into iTregs (51, 52). Furthermore, these tumor-infiltrating iTreg have been shown to have greater suppressive activity that nTreg, both in terms of the levels of suppression as well as the mechanisms used (22, 53–55). "
[Show abstract][Hide abstract] ABSTRACT: The importance of regulatory T cells (Tregs) in balancing the effector arm of the immune system is well documented, playing a central role in preventing autoimmunity, facilitating graft tolerance following organ transplantation, and having a detrimental impact on the development of anti-tumor immunity. These regulatory responses use a variety of mechanisms to mediate suppression, including soluble factors. While IL-10 and TGF-β are the most commonly studied immunosuppressive cytokines, the recently identified IL-35 has been shown to have potent suppressive function in vitro and in vivo. Furthermore, not only does IL-35 have the ability to directly suppress effector T cell responses, it is also able to expand regulatory responses by propagating infectious tolerance and generating a potent population of IL-35-expressing inducible Tregs. In this review, we summarize research characterizing the structure and function of IL-35, examine its role in disease, and discuss how it can contribute to the induction of a distinct population of inducible Tregs.
Frontiers in Immunology 10/2013; 4:315. DOI:10.3389/fimmu.2013.00315
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