A Unique Subset of CD4+CD25highFoxp3+ T Cells Secreting Interleukin-10 and Transforming Growth Factor-β1 Mediates Suppression in the Tumor Microenvironment

Strauss, Laura; Bergmann, Christoph; Szczepański, Mirosław J.; Gooding, William E.; Johnson, Jonas T.; Whiteside, Theresa L.

doi:10.1158/1078-0432.ccr-07-0472

Cited by 396 publications

(334 citation statements)

References 42 publications

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“…However, macrophages are not the sole IL-10 source in tumors. Studies in human cancer have shown that Treg cells recruited at tumor sites produce abundant IL-10 [37,38], which may work as the main mediator of Treg-cell functional suppression [37]. Conversely, in a murine tumor model, others have shown that CD25 1 -cell depletion and IL-10 receptor blockade exert distinct, though partially overlapping, effects in suppressing DC activation and anti-tumor CD8 1 response [13].…”

Section: Discussionmentioning

confidence: 99%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4 1 populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cellmediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor. 3615The tumor microenvironment is characterized by an immunosuppressive cytokine milieu, which promotes immune tolerance and tumor growth. Treg cells secrete interleukin 10 (IL-10), which plays a critical role in suppressing immune responses and in particular the maturation of fully competent DCs [13][14][15]. Among tumor-infiltrating Teff cells, the subpopulation of effector memory T (Tem) cells is the most abundant. Tem cells are CD4 1 CD44 high CD62L low lymphocytes excluded from resting lymph nodes and mainly localized in peripheral tissues; upon stimulation they rapidly activate and secrete effector cytokines like IFN-g, but they have limited proliferative capacity [16]. In experimental models of immune activation, Tem cells constitutively express CD40L at levels sufficient to induce DC activation in an antigen-independent manner [17]. The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].In this study we have investigated the mechanisms by which OX86 modulates Treg-and Teff-cell functions and their reciprocal interactions with DCs at the tumor site. We propose a model of the tumor microenvironment in which, after OX86 treatment, DCs receive a lower IL-10-mediated inhibition by Treg cells on the one hand, and a stronger stimulation from Tem cells, via the CD40/CD40L axis, on the other. In this favorable condition, DCs acquire a stronger migratory ability toward the draining LNs (dLNs), thus inducing a specific anti-tumor immune response. ResultsIntratumoral ...

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Section: Discussionmentioning

confidence: 99%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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“…W światowym piśmiennictwie liczni badacze wskazują na znaczącą rolę badań nad zaburzeniami układu odpornościowego w przebiegu choroby nowotworowej [10][11][12][13][14][15][16][17][18][19][20][21][22]. Dokładne poznanie i zrozumienie mechanizmów tych zaburzeń stwarza szansę na wskazanie immunologicznych wykładników związanych z klinicznym przebiegiem choroby, na podstawie których można by oceniać stopień inwazyjności zmian nowotworowych i podejmować właści-we decyzje terapeutyczne.…”

Section: Wstępunclassified

“…Znaczenie tych czynników w onkologii klinicznej opiera się na ich różnorodnych właściwościach modyfikowania odpowiedzi immunologicznej. Najczęściej wskazywanymi cytokinami, które mogą mieć znaczenie w przebiegu choroby nowotworowej, są interleukiny o właściwościach prozapalnych IL-6 i IL-8 oraz cytokiny IL-10 i TGF-β o działaniu regulatorowym i immunosupresyjnym [19,21,23,[33][34][35]. Prozapalne cytokiny IL-6 i IL-8 wydzielane przez komórki nowotworowe, określane jako czynniki promujące kancerogenezę i wzrost guza nowotworowego, oraz cytokiny o właściwościach proonkogennych i prometastatycznych sprzyjają w szczególny sposób progresji choroby nowotworowej, w tym HNSCC [18,23,[35][36][37][38].…”

Section: Wstępunclassified

Secretion of inflammatory and regulatory cytokines and the association with depth and type of tumour invasion in patients with cancer of the larynx

Starska¹,

Lewy-Trenda²,

Woś³

et al. 2010

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“…1) are also seen in the circulation [38,39]. Tregs within the tumor mediate suppression through TGF-β and/or IL-10, compromising tumor-specific CD8 + responses [38].…”

Section: Regulatory T Cells and Tgf-βmentioning

confidence: 99%

“…In one report, increased Treg prevalence in HNSCC was surprisingly associated with a better disease prognosis [46], requiring further elucidation. Response to treatment has been linked to an expansion of Tregs in the circulation, although this may not be indicative of what occurs within the tumor sites [38]. The balance between helper T cells and Treg has also been shown to be a critical parameter in the response to cancer vaccines [47].…”

Section: Regulatory T Cells and Tgf-βmentioning

confidence: 99%

TGF-β and tumors—an ill-fated alliance

Moutsopoulos

Wen

Wahl

2008

Current Opinion in Immunology

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A Unique Subset of CD4+CD25highFoxp3+ T Cells Secreting Interleukin-10 and Transforming Growth Factor-β1 Mediates Suppression in the Tumor Microenvironment

Cited by 396 publications

References 42 publications

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Secretion of inflammatory and regulatory cytokines and the association with depth and type of tumour invasion in patients with cancer of the larynx

TGF-β and tumors—an ill-fated alliance

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