Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity
<p>Abstract</p> <p>Background</p> <p>Rapamycin, an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. However, the role of Rapamycin-induced immune suppression on tumor progression has not...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2008-06-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/8/176 |
| _version_ | 1818755566508441600 |
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| author | Telford William Viskova Natalia Y Wright Mollie H Mariotti Jacopo Svirshchevskaya Elena V Fowler Daniel H Varticovski Lyuba |
| author_facet | Telford William Viskova Natalia Y Wright Mollie H Mariotti Jacopo Svirshchevskaya Elena V Fowler Daniel H Varticovski Lyuba |
| author_sort | Telford William |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Rapamycin, an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. However, the role of Rapamycin-induced immune suppression on tumor progression has not been examined.</p> <p>Methods</p> <p>We developed a transplantation model for generation of mammary tumors in syngeneic recipients that can be used to address the role of the immune system on tumor progression. We examined the effect of Rapamycin on the immune system and growth of MMTV-driven Wnt-1 mammary tumors which were transplanted into irradiated and bone marrow-reconstituted, or naïve mice.</p> <p>Results</p> <p>Rapamycin induced severe immunosuppression and significantly delayed the growth of Wnt-1 tumors. T cell depletion in spleen and thymus and reduction in T cell cytokine secretion were evident within 7 days of therapy. By day 20, splenic but not thymic T cell counts, and cytokine secretion recovered. We determined whether adoptive T cell therapy enhances the anti-cancer effect using <it>ex vivo </it>generated Rapamycin-resistant T cells. However, T cell transfer during Rapamycin therapy did not improve the outcome relative to drug therapy alone. Thus, we could not confirm that suppression of T cell immunity contributes to tumor growth in this model. Consistent with suppression of the mTOR pathway, decreased 4E-BP1, p70 S6-kinase, and S6 protein phosphorylation correlated with a decrease in Wnt-1 tumor cell proliferation.</p> <p>Conclusion</p> <p>Rapamycin has a direct anti-tumor effect on Wnt-1 breast cancer <it>in vivo </it>that involves inhibition of the mTOR pathway at doses that also suppress host immune responses.</p> |
| first_indexed | 2024-12-18T05:41:11Z |
| format | Article |
| id | doaj.art-79484ad2b45045b6b3144810299d0f1f |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-18T05:41:11Z |
| publishDate | 2008-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-79484ad2b45045b6b3144810299d0f1f2022-12-21T21:19:10ZengBMCBMC Cancer1471-24072008-06-018117610.1186/1471-2407-8-176Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunityTelford WilliamViskova Natalia YWright Mollie HMariotti JacopoSvirshchevskaya Elena VFowler Daniel HVarticovski Lyuba<p>Abstract</p> <p>Background</p> <p>Rapamycin, an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. However, the role of Rapamycin-induced immune suppression on tumor progression has not been examined.</p> <p>Methods</p> <p>We developed a transplantation model for generation of mammary tumors in syngeneic recipients that can be used to address the role of the immune system on tumor progression. We examined the effect of Rapamycin on the immune system and growth of MMTV-driven Wnt-1 mammary tumors which were transplanted into irradiated and bone marrow-reconstituted, or naïve mice.</p> <p>Results</p> <p>Rapamycin induced severe immunosuppression and significantly delayed the growth of Wnt-1 tumors. T cell depletion in spleen and thymus and reduction in T cell cytokine secretion were evident within 7 days of therapy. By day 20, splenic but not thymic T cell counts, and cytokine secretion recovered. We determined whether adoptive T cell therapy enhances the anti-cancer effect using <it>ex vivo </it>generated Rapamycin-resistant T cells. However, T cell transfer during Rapamycin therapy did not improve the outcome relative to drug therapy alone. Thus, we could not confirm that suppression of T cell immunity contributes to tumor growth in this model. Consistent with suppression of the mTOR pathway, decreased 4E-BP1, p70 S6-kinase, and S6 protein phosphorylation correlated with a decrease in Wnt-1 tumor cell proliferation.</p> <p>Conclusion</p> <p>Rapamycin has a direct anti-tumor effect on Wnt-1 breast cancer <it>in vivo </it>that involves inhibition of the mTOR pathway at doses that also suppress host immune responses.</p>http://www.biomedcentral.com/1471-2407/8/176 |
| spellingShingle | Telford William Viskova Natalia Y Wright Mollie H Mariotti Jacopo Svirshchevskaya Elena V Fowler Daniel H Varticovski Lyuba Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity BMC Cancer |
| title | Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity |
| title_full | Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity |
| title_fullStr | Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity |
| title_full_unstemmed | Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity |
| title_short | Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity |
| title_sort | rapamycin delays growth of wnt 1 tumors in spite of suppression of host immunity |
| url | http://www.biomedcentral.com/1471-2407/8/176 |
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