Blockade of TGF-β signaling to enhance the antitumor response is accompanied by dysregulation of the functional activity of CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> and CD4<sup>+</sup>CD25<sup>−</sup>Foxp3<sup>+</sup> T cells
<h3>Background</h3><p dir="ltr">The pleiotropic cytokine, transforming growth factor (TGF)-β, and CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (Tregs) play a critical role in actively suppressing antitumor immune...
محفوظ في:
| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , |
| منشور في: |
2019
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| الموضوعات: | |
| الوسوم: |
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| الملخص: | <h3>Background</h3><p dir="ltr">The pleiotropic cytokine, transforming growth factor (TGF)-β, and CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (Tregs) play a critical role in actively suppressing antitumor immune responses. Evidence shows that TGF-β produced by tumor cells promotes tolerance via expansion of Tregs. Our group previously demonstrated that blockade of TGF-β signaling with a small molecule TGF-β receptor I antagonist (SM16) inhibited primary and metastatic tumor growth in a T cell dependent fashion. In the current study, we evaluated the effect of SM16 on Treg generation and function. </p><h3>Methods</h3><p dir="ltr">Using BALB/c, FoxP3eGFP and Rag<sup>−/−</sup> mice, we performed FACS analysis to determine if SM16 blocked de novo TGF-β-induced Treg generation in vitro and in vivo. CD4<sup>+</sup> T cells from lymph node and spleen were isolated from control mice or mice maintained on SM16 diet, and flow cytometry analysis was used to detect the frequency of CD4<sup>+</sup>CD25<sup>−</sup>FoxP3<sup>+</sup> and CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> T cells. In vitro suppression assays were used to determine the ability to suppress naive T cell proliferation in vitro of both CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> and CD4<sup>+</sup>CD25<sup>−</sup>FoxP3<sup>+</sup> T cell sub-populations. We then examined whether SM16 diet exerted an inhibitory effect on primary tumor growth and correlated with changes in FoxP3<sup>+</sup>expression. ELISA analysis was used to measure IFN-γ levels after 72 h co-culture of CD4<sup>+</sup>CD25<sup>+</sup> T cells from tumor-bearing mice on control or SM16 diet with CD4<sup>+</sup>CD25<sup>−</sup> T cells from naive donors. </p><h3>Results</h3><p dir="ltr">SM16 abrogates TGF-β-induced Treg generation in vitro but does not prevent global homeostatic expansion of CD4<sup>+</sup>T cell sub-populations in vivo. Instead, SM16 treatment causes expansion of a population of CD4<sup>+</sup>CD25<sup>−</sup>Foxp3<sup>+</sup> Treg-like cells without significantly altering the overall frequency of Treg in lymphoreplete naive and tumor-bearing mice. Importantly, both the CD4<sup>+</sup>CD25<sup>−</sup>Foxp3<sup>+</sup> T cells and the CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> Tregs in mice receiving SM16 diet exhibited diminished ability to suppress naive T cell proliferation in vitro compared to Treg from mice on control diet. </p><h3>Conclusions</h3><p dir="ltr">These findings suggest that blockade of TGF-β signaling is a potentially useful strategy for blunting Treg function to enhance the anti-tumor response. Our data further suggest that the overall dampening of Treg function may involve the expansion of a quiescent Treg precursor population, which is CD4<sup>+</sup>CD25<sup>−</sup>Foxp3<sup>+</sup>.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Translational Medicine<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1186/s12967-019-1967-3" target="_blank">http://dx.doi.org/10.1186/s12967-019-1967-3</a></p> |
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