A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells
The activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. Increasing evidence also suggests that regulatory T cells (Tregs) are i...
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2008
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| Online Access: | http://hdl.handle.net/10725/6475 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://link.springer.com/article/10.1007/s00262-008-0618-y |
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| _version_ | 1864513479863435264 |
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| author | Abou-Ghazal, Mohamed K. |
| author2 | Kong, Ling-Yuan Wei, Jun Sharma, Amit K. Barr, Jason Fokt, Izabela Weinberg, Jeffrey Rao, Ganesh Grimm, Elizabeth Priebe, Waldemar Heimberger, Amy B. |
| author2_role | author author author author author author author author author author |
| author_facet | Abou-Ghazal, Mohamed K. Kong, Ling-Yuan Wei, Jun Sharma, Amit K. Barr, Jason Fokt, Izabela Weinberg, Jeffrey Rao, Ganesh Grimm, Elizabeth Priebe, Waldemar Heimberger, Amy B. |
| author_role | author |
| dc.creator.none.fl_str_mv | Abou-Ghazal, Mohamed K. Kong, Ling-Yuan Wei, Jun Sharma, Amit K. Barr, Jason Fokt, Izabela Weinberg, Jeffrey Rao, Ganesh Grimm, Elizabeth Priebe, Waldemar Heimberger, Amy B. |
| dc.date.none.fl_str_mv | 2008 2017-11-02T07:55:37Z 2017-11-02T07:55:37Z 2017-11-02 |
| dc.identifier.none.fl_str_mv | 1432-0851 http://hdl.handle.net/10725/6475 Kong, L. Y., Wei, J., Sharma, A. K., Barr, J., Abou-Ghazal, M. K., Fokt, I., ... & Heimberger, A. B. (2009). A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells. Cancer immunology, immunotherapy, 58(7), 1023-1032. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://link.springer.com/article/10.1007/s00262-008-0618-y |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Cancer Immunology, Immunotherapy |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | The activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. Increasing evidence also suggests that regulatory T cells (Tregs) are important in suppressing anti-tumor immunity and play a dominant role in negating efficacious immunotherapy approaches. We hypothesized that WP1066, a novel inhibitor of STAT3 signaling, reverses immune suppression through the inhibition of Tregs and that this contributes to the antitumor activity of this agent against melanoma brain metastases. We found that the mean percentage of peripheral blood mononuclear cells expressing phosphorylated STAT3 (p-STAT3) was significantly elevated in samples from patients with melanoma brain metastases compared to healthy donors, 16.13 ± 2.48% versus 4.17 ± 1.79%. The p-STAT3 inhibitor WP1066 enhanced CD3+ (which contained Tregs) but not CD8+ T cell cytotoxicity against human A375 melanoma cells, indicating that this p-STAT3 blockade agent did not directly activate CD8+ T cells. Furthermore, the p-STAT3 inhibitor did not enhance the cytotoxicity of CD3+CD25− T cells (from which Tregs were excluded), indicating that the enhanced cytotoxicity of WP1066 is secondary to its inhibition of Tregs. This was confirmed by demonstrating that WP1066 inhibited FoxP3+ Treg induction in a dose-dependent manner. Moreover, CD3+ T cells exhibited markedly enhanced levels of phosphorylated ZAP-70, a critical proximal signal in T cell activation, after exposure to WP1066. Similar effects were not observed in Treg-depleted CD3+CD25− T cell populations, confirming that the T cell activation by WP compounds is secondary to their inhibition of the Tregs. These results suggest that WP1066 enhances T cell cytotoxicity against melanoma through inhibition of Tregs. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_ea737c20480b1a8d66a47022418e0e47 |
| identifier_str_mv | 1432-0851 Kong, L. Y., Wei, J., Sharma, A. K., Barr, J., Abou-Ghazal, M. K., Fokt, I., ... & Heimberger, A. B. (2009). A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells. Cancer immunology, immunotherapy, 58(7), 1023-1032. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/6475 |
| publishDate | 2008 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cellsAbou-Ghazal, Mohamed K.Kong, Ling-YuanWei, JunSharma, Amit K.Barr, JasonFokt, IzabelaWeinberg, JeffreyRao, GaneshGrimm, ElizabethPriebe, WaldemarHeimberger, Amy B.The activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. Increasing evidence also suggests that regulatory T cells (Tregs) are important in suppressing anti-tumor immunity and play a dominant role in negating efficacious immunotherapy approaches. We hypothesized that WP1066, a novel inhibitor of STAT3 signaling, reverses immune suppression through the inhibition of Tregs and that this contributes to the antitumor activity of this agent against melanoma brain metastases. We found that the mean percentage of peripheral blood mononuclear cells expressing phosphorylated STAT3 (p-STAT3) was significantly elevated in samples from patients with melanoma brain metastases compared to healthy donors, 16.13 ± 2.48% versus 4.17 ± 1.79%. The p-STAT3 inhibitor WP1066 enhanced CD3+ (which contained Tregs) but not CD8+ T cell cytotoxicity against human A375 melanoma cells, indicating that this p-STAT3 blockade agent did not directly activate CD8+ T cells. Furthermore, the p-STAT3 inhibitor did not enhance the cytotoxicity of CD3+CD25− T cells (from which Tregs were excluded), indicating that the enhanced cytotoxicity of WP1066 is secondary to its inhibition of Tregs. This was confirmed by demonstrating that WP1066 inhibited FoxP3+ Treg induction in a dose-dependent manner. Moreover, CD3+ T cells exhibited markedly enhanced levels of phosphorylated ZAP-70, a critical proximal signal in T cell activation, after exposure to WP1066. Similar effects were not observed in Treg-depleted CD3+CD25− T cell populations, confirming that the T cell activation by WP compounds is secondary to their inhibition of the Tregs. These results suggest that WP1066 enhances T cell cytotoxicity against melanoma through inhibition of Tregs.PublishedN/A2017-11-02T07:55:37Z2017-11-02T07:55:37Z20082017-11-02Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1432-0851http://hdl.handle.net/10725/6475Kong, L. Y., Wei, J., Sharma, A. K., Barr, J., Abou-Ghazal, M. K., Fokt, I., ... & Heimberger, A. B. (2009). A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells. Cancer immunology, immunotherapy, 58(7), 1023-1032.http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.phphttps://link.springer.com/article/10.1007/s00262-008-0618-yenCancer Immunology, Immunotherapyinfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/64752021-03-19T10:03:26Z |
| spellingShingle | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells Abou-Ghazal, Mohamed K. |
| status_str | publishedVersion |
| title | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells |
| title_full | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells |
| title_fullStr | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells |
| title_full_unstemmed | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells |
| title_short | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells |
| title_sort | A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells |
| url | http://hdl.handle.net/10725/6475 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://link.springer.com/article/10.1007/s00262-008-0618-y |