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: | |
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| _version_ | 1864513555881000960 |
|---|---|
| author | Magdalena J. Polanczyk (14153283) |
| author2 | Edwin Walker (4705993) Daniel Haley (14153286) Bella S. Guerrouahen (14153289) Emmanuel T. Akporiaye (8335038) |
| author2_role | author author author author |
| author_facet | Magdalena J. Polanczyk (14153283) Edwin Walker (4705993) Daniel Haley (14153286) Bella S. Guerrouahen (14153289) Emmanuel T. Akporiaye (8335038) |
| author_role | author |
| dc.creator.none.fl_str_mv | Magdalena J. Polanczyk (14153283) Edwin Walker (4705993) Daniel Haley (14153286) Bella S. Guerrouahen (14153289) Emmanuel T. Akporiaye (8335038) |
| dc.date.none.fl_str_mv | 2019-07-09T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s12967-019-1967-3 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Blockade_of_TGF-_signaling_to_enhance_the_antitumor_response_is_accompanied_by_dysregulation_of_the_functional_activity_of_CD4_CD25_Foxp3_and_CD4_CD25_Foxp3_T_cells/21598446 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Immunology Medical biochemistry and metabolomics Oncology and carcinogenesis TGF-β SM16 Mice Treg subsets Anti-tumor response |
| dc.title.none.fl_str_mv | 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 |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <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> |
| eu_rights_str_mv | openAccess |
| id | Manara2_fd3a1e6fd39563b0ba0b86f7dff09845 |
| identifier_str_mv | 10.1186/s12967-019-1967-3 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/21598446 |
| publishDate | 2019 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | 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 cellsMagdalena J. Polanczyk (14153283)Edwin Walker (4705993)Daniel Haley (14153286)Bella S. Guerrouahen (14153289)Emmanuel T. Akporiaye (8335038)Biological sciencesBiochemistry and cell biologyBiomedical and clinical sciencesImmunologyMedical biochemistry and metabolomicsOncology and carcinogenesisTGF-βSM16MiceTreg subsetsAnti-tumor response<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>2019-07-09T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s12967-019-1967-3https://figshare.com/articles/journal_contribution/Blockade_of_TGF-_signaling_to_enhance_the_antitumor_response_is_accompanied_by_dysregulation_of_the_functional_activity_of_CD4_CD25_Foxp3_and_CD4_CD25_Foxp3_T_cells/21598446CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/215984462019-07-09T06:00:00Z |
| spellingShingle | 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 Magdalena J. Polanczyk (14153283) Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Immunology Medical biochemistry and metabolomics Oncology and carcinogenesis TGF-β SM16 Mice Treg subsets Anti-tumor response |
| status_str | publishedVersion |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Immunology Medical biochemistry and metabolomics Oncology and carcinogenesis TGF-β SM16 Mice Treg subsets Anti-tumor response |