IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

Sim, Geok Choo; Martín‐Orozco, Natalia; Jin, Lei; Yang, Yantao; Wu, Sheng; Washington, Edwina; Sanders, Deborah A.; Lacey, Carol; Wang, Yijun; Vence, Luis M.; Hwu, Patrick; Radvanyi, Laszlo G.

doi:10.1172/jci46266

Cited by 195 publications

(190 citation statements)

References 64 publications

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“…4E). This reduction was restored by IL-2 treatment, confirming the dependence of ICOS expression on IL-2 (22). Next, we assessed the suppressive function of the Tregs by culturing them with CD4 +…”

Section: Il-2 Restores the Cnis-induced Homeostatic Dysfunction Of Trsupporting

confidence: 54%

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

Whitehouse

Gray

Mastoridis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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+ Tregs constitute a heterogeneous lymphocyte subpopulation essential for curtailing effector T cells and establishing peripheral tolerance. Calcineurin inhibitors (CNIs) are among the most effective agents in controlling effector T-cell responses in humans. However, CNIs also reduce the size of the Treg pool. The functional consequences of this negative effect and the mechanisms responsible remain to be elucidated. We report here that CNIs compromise the overall Treg immunoregulatory capacity to a greater extent than would be predicted by the reduction in the size of the Treg compartment, given that they selectively promote the apoptosis of the resting and activated Treg subsets that are known to display the most powerful suppressive function. These effects are caused by reduced access to IL-2, because Tregs remain capable of translocating NFAT even in the presence of high CNI levels. Exogenous IL-2 restores the phenotypic changes and overall gene-expression effects exerted by CNIs and can even promote Treg expansion by enhancing antiapoptotic Bcl-2 expression. In a skin transplant model, the addition of IL-2 synergizes with CNIs treatment, promoting intragraft accumulation of Tregs and prolonged allograft survival. Hence, the combination of IL-2 and CNIs constitutes an optimal immunomodulatory regimen that enhances the pool of suppressive Treg subsets while effectively controlling cytopathic T cells.regulatory T cells | transplantation | IL-2 therapy | calcineurin inhibitors |

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Section: Il-2 Restores the Cnis-induced Homeostatic Dysfunction Of Trsupporting

confidence: 54%

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

Whitehouse

Gray

Mastoridis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…High-dose IL2 has been successful in a few cancer patients, but it was also shown to expand P-PB ICOS + Tregs, leading to adverse outcomes (56,57). In contrast, low-dose IL2 therapy has demonstrated efficacy for treating autoimmune diseases where it functions by increasing Tregs (39), with IL2 neutralization in animal models provoking autoimmunity (58).…”

Section: Discussionmentioning

confidence: 99%

CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer

Gu-Trantien¹,

Migliori²,

Buisseret³

et al. 2017

JCI Insight

291

313

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“…In humans, only a small fraction of Tregs express CD73 in steady-state ( 12 ). In response to IL2, however, the majority of human Tregs express both CD39 and CD73 ( 13 ). Increased Treg abundance in response to hypoxia via upregulated FOXP3 gene expression represents an additional mechanism of HIF1α regulatory control.…”

Section: Adenosine-abundant Tumor Microenvironmentmentioning

confidence: 99%

Targeting Cancer-Derived Adenosine:New Therapeutic Approaches

et al. 2014

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CD73 generation of immunosuppressive adenosine within the hypoxic tumor microenvironment causes dysregulation of immune cell infi ltrates, resulting in tumor progression, metastases, and poor disease outcomes. Therapies targeted toward the adenosinergic pathway, such as antibodies targeting CD73 and CD39, have proven effi cacy in mouse tumor models; however, humanized versions are only in preliminary development. In contrast, A 2A adenosine receptor antagonists have progressed to late-stage clinical trials in Parkinson disease, yet evidence of their role in oncology is limited. This review will compare the merits and challenges of these therapeutic approaches, identifying tumor indications and combinations that may be fruitful as they progress to the clinic.Signifi cance: High concentrations of immunosuppressive adenosine have been reported in cancers, and adenosine is implicated in the growth of tumors. This brief review delineates the current treatment strategies and tumor subtypes that will benefi t from targeting adenosinergic pathways, alone or in combination with contemporary approaches to cancer treatment. Cancer Discov; 4(8);

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IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

Abstract: High-dose (HD) IL-2 therapy in patients with

Cited by 195 publications

References 64 publications

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer

Targeting Cancer-Derived Adenosine:New Therapeutic Approaches

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