A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis.
<h4>Background</h4>K-Ras mutations are characteristic of human lung adenocarcinomas and occur almost exclusively in smokers. In preclinical models, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgeni...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0005061&type=printable |
| _version_ | 1826861504160333824 |
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| author | Courtney A Granville Regan M Memmott Andria Balogh Jacopo Mariotti Shigeru Kawabata Wei Han Jaclyn Lopiccolo Jason Foley David J Liewehr Seth M Steinberg Daniel H Fowler M Christine Hollander Phillip A Dennis |
| author_facet | Courtney A Granville Regan M Memmott Andria Balogh Jacopo Mariotti Shigeru Kawabata Wei Han Jaclyn Lopiccolo Jason Foley David J Liewehr Seth M Steinberg Daniel H Fowler M Christine Hollander Phillip A Dennis |
| author_sort | Courtney A Granville |
| collection | DOAJ |
| description | <h4>Background</h4>K-Ras mutations are characteristic of human lung adenocarcinomas and occur almost exclusively in smokers. In preclinical models, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgenic mice. Because these mutations confer resistance to commonly used cytotoxic chemotherapies and targeted agents, effective therapies that target K-Ras are needed. Inhibitors of mTOR such as rapamycin can prevent K-Ras-driven lung tumorigenesis and alter the proportion of cytotoxic and Foxp3+ regulatory T cells, suggesting that lung-associated T cells might be important for tumorigenesis.<h4>Methods</h4>Lung tumorigenesis was studied in three murine models that depend on mutant K-Ras; a tobacco carcinogen-driven model, a syngeneic inoculation model, and a transgenic model. Splenic and lung-associated T cells were studied using flow cytometry and immunohistochemistry. Foxp3+ cells were depleted using rapamycin, an antibody, or genetic ablation.<h4>Results</h4>Exposure of A/J mice to a tobacco carcinogen tripled lung-associated Foxp3+ cells prior to tumor development. At clinically relevant concentrations, rapamycin prevented this induction and reduced lung tumors by 90%. In A/J mice inoculated with lung adenocarcinoma cells resistant to rapamycin, antibody-mediated depletion of Foxp3+ cells reduced lung tumorigenesis by 80%. Likewise, mutant K-Ras transgenic mice lacking Foxp3+ cells developed 75% fewer lung tumors than littermates with Foxp3+ cells.<h4>Conclusions</h4>Foxp3+ regulatory T cells are required for K-Ras-mediated lung tumorigenesis in mice. These studies support clinical testing of rapamycin or other agents that target Treg in K-Ras driven human lung cancer. |
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| format | Article |
| id | doaj.art-8db6ea945f494ba598f5f20f7720f5e3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2025-02-16T20:23:20Z |
| publishDate | 2009-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8db6ea945f494ba598f5f20f7720f5e32025-01-21T05:31:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-01-0143e506110.1371/journal.pone.0005061A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis.Courtney A GranvilleRegan M MemmottAndria BaloghJacopo MariottiShigeru KawabataWei HanJaclyn LopiccoloJason FoleyDavid J LiewehrSeth M SteinbergDaniel H FowlerM Christine HollanderPhillip A Dennis<h4>Background</h4>K-Ras mutations are characteristic of human lung adenocarcinomas and occur almost exclusively in smokers. In preclinical models, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgenic mice. Because these mutations confer resistance to commonly used cytotoxic chemotherapies and targeted agents, effective therapies that target K-Ras are needed. Inhibitors of mTOR such as rapamycin can prevent K-Ras-driven lung tumorigenesis and alter the proportion of cytotoxic and Foxp3+ regulatory T cells, suggesting that lung-associated T cells might be important for tumorigenesis.<h4>Methods</h4>Lung tumorigenesis was studied in three murine models that depend on mutant K-Ras; a tobacco carcinogen-driven model, a syngeneic inoculation model, and a transgenic model. Splenic and lung-associated T cells were studied using flow cytometry and immunohistochemistry. Foxp3+ cells were depleted using rapamycin, an antibody, or genetic ablation.<h4>Results</h4>Exposure of A/J mice to a tobacco carcinogen tripled lung-associated Foxp3+ cells prior to tumor development. At clinically relevant concentrations, rapamycin prevented this induction and reduced lung tumors by 90%. In A/J mice inoculated with lung adenocarcinoma cells resistant to rapamycin, antibody-mediated depletion of Foxp3+ cells reduced lung tumorigenesis by 80%. Likewise, mutant K-Ras transgenic mice lacking Foxp3+ cells developed 75% fewer lung tumors than littermates with Foxp3+ cells.<h4>Conclusions</h4>Foxp3+ regulatory T cells are required for K-Ras-mediated lung tumorigenesis in mice. These studies support clinical testing of rapamycin or other agents that target Treg in K-Ras driven human lung cancer.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0005061&type=printable |
| spellingShingle | Courtney A Granville Regan M Memmott Andria Balogh Jacopo Mariotti Shigeru Kawabata Wei Han Jaclyn Lopiccolo Jason Foley David J Liewehr Seth M Steinberg Daniel H Fowler M Christine Hollander Phillip A Dennis A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS ONE |
| title | A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. |
| title_full | A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. |
| title_fullStr | A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. |
| title_full_unstemmed | A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. |
| title_short | A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. |
| title_sort | central role for foxp3 regulatory t cells in k ras driven lung tumorigenesis |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0005061&type=printable |
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