Induced regulatory T cells in inhibitory microenvironments created by cancer

Abstract

Introduction Regulatory T cells (Tregs) accumulating in the peripheral circulation and tumor sites of patients contribute to tumor escape from the host immune system. Tregs encompass subsets of immune cells with distinct phenotypic and functional properties. Whereas natural (n) or thymic-derived (t) Tregs regulate responses to self-antigens, inducible (i) or peripheral (p) Tregs generated and expanded in regulatory microenvironments control immune responses to a broad variety of antigens. Areas covered Tregs accumulating in the tumor microenvironment (TME) are contextually regulated. They acquire phenotypic and functional attributes imposed by the inhibitory molecular pathways operating in situ. Several molecular pathways active in human cancer are reviewed. The pathways may differ from one tumor to another, and environmentally induced Tregs may be functionally distinct. Potential therapeutic strategies for selective silencing of iTregs are considered in the light of the newly acquired understanding of their phenotypic and functional diversity. Expert opinion Human Tregs accumulating in cancer comprise ‘bad’ subsets, which inhibit antitumor immunity, and ‘good’ anti-inflammatory subsets, which maintain tolerance to self and benefit the host. Future therapeutic strategies targeting Tregs will need to discriminate between these Treg subsets and will need to consider reprogramming strategies instead of Treg elimination. Re-establishment of effective antitumor immune responses in cancer patients without disturbing a normal homeostatic T-cell balance will greatly benefit from insights into inhibitory pathways engaged by human tumors.

Restricting Glutamine or Glutamine-Dependent Purine and Pyrimidine Syntheses Promotes Human T Cells with High FOXP3 Expression and Regulatory Properties

“…Our data might help to understand, for example, why functional Tregs are well maintained in mycophenolate mofetil-treated transplant patients and might further hint at Treg-compatible immunosuppressive treatments (52). On the opposite side of the coin, cancer drugs targeting these pathways could possibly have a suboptimal therapeutic effect in some cases (53,54). Furthermore, our results might help to explain why Tregs may thrive well within tumors if these are addicted to Gln or, similar to activated FOXP3 hi CD4 T cells in our studies, are also resistant to Gln deprivation through utilizing GS (55).…”

Intratumoral FoxP3 expression is associated with angiogenesis and prognosis in malignant canine mammary tumors

“…Tregs have emerged as key players in the development and maintenance of peripheral immune tolerance (Elkord et al, 2010;Piersma et al, 2008). Normally these cells can work for prevention of harmful autoimmune responses, however can also interfere with beneficial immune responses such as anti-tumor immunity (Elkord et al, 2010;Nishikawa and Sakaguchi, 2014;Whiteside, 2014). Tregs can secrete inhibitory cytokines, such as IL-10, TGF-β which induce the reduction of both CD8+ T lymphocytes and natural killer (NK) cells cytotoxic activities, thus contributing for anti-tumor immune suppression (Chen et al, 2005;Ghiringhelli et al, 2005;Strauss et al, 2007).…”

“…Tregs can secrete inhibitory cytokines, such as IL-10, TGF-β which induce the reduction of both CD8+ T lymphocytes and natural killer (NK) cells cytotoxic activities, thus contributing for anti-tumor immune suppression (Chen et al, 2005;Ghiringhelli et al, 2005;Strauss et al, 2007). Recent studies have shown that Tregs are implicated in inducing tumor progression (Kim et al, 2012;Merlo et al, 2009;Whiteside, 2014;Yamaguchi and Sakaguchi, 2006;Zou, 2006). Tumor antigens are recognized by autologous T cells (Pardoll, 2003) and are regarded as self by Tregs that actively promote their tolerance (Cao, 2010).…”

Clinical Impact of Regulatory T cells (Treg) in Cancer and HIV

“…As recently discussed, these include, e.g., the adenosine/PGE 2 , the TGF-β, the IL-2/IL-R or the NRP-1/semaph-4a pathways and perhaps many others [31]. Blocking of these pathways with neutralizing Abs or pharmacologic inhibitors has been broadly referred to as the "blocking the inhibitors" strategy [57].…”