Induced and natural regulatory T cells in human cancer

ArticleinExpert opinion on biological therapy 12(10):1383-97 · July 2012with14 Reads
DOI: 10.1517/14712598.2012.707184 · Source: PubMed
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.
    • "In the majority of studies, Treg assessment is restricted to phenotypic characterization and quantification. Yet, the absence of exclusive and highly specific Treg markers in humans and the presence of a high number of distinct subpopulations [120] complicates the analysis, leads to a multitude of reported phenotypic Treg definitions, as well as to a blurred picture regarding the association between Tregs and clinical outcome (reviewed by Whiteside et al. [117,119]). Especially since information on the suppressive capacity of the identified Treg population often is lacking in these studies, assessment of the suppressive capacity of each of the identified Treg populations, therefore, seems essential in the context of immunomonitoring. "
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    • "Hence, the administration of SOCE blockers would target a signalling pathway that is ineffective and is unlikely to further aggravate the scenario. Moreover, a subsequent investigation reported that Orai1 inhibition (with BTP2/YM-58483) abrogates forkhead box protein 3 (FoxP3) expression in the highly suppressive, therapy-resistant inducible T regulatory cells (iTreg) [159], which in turn down-regulate effector T cells to favor tumour progression [160]. It has been demonstrated that iTreg depletion enhances endogenous anti-tumour immunity, which led to the proposal that blocking iTreg could improve the outcome of anti-cancer treatments [157]. "
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    • "In contrast to CD4 + CD25 hi Foxp3 + naturalTreg (nTreg), these Tr1 cells exhibit a CD4 + CD25 − Foxp3 low/neg phenotype and suppress target cells through IL-10 and transforming growth factor (TGF)-β secretion as opposed to contact-dependent suppression. Hence, monitoring of Tr1 rather than nTreg may be more relevant in the cancer setting [21]. The presence of tumor antigen–specific T cells as determined by tetramer analyses, or the recently developed combination of ultraviolet-induced peptide exchange and peptide-major histocompatibility complex (MHC) combinatorial coding, may further provide information on the success of immune therapy to expand pre-existing T cells or broaden the T-cell repertoire against tumor and/or virus-associated antigens [22]. "
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