Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models
The adhesion protein Kindlin-1 is over-expressed in breast cancer where it is associated with metastasis-free survival; however, the mechanisms involved are poorly understood. Here, we report that Kindlin-1 promotes anti-tumor immune evasion in mouse models of breast cancer. Deletion of Kindlin-1 in...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/85739 |
| _version_ | 1827987604355678208 |
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| author | Emily R Webb Georgia L Dodd Michaela Noskova Esme Bullock Morwenna Muir Margaret C Frame Alan Serrels Valerie G Brunton |
| author_facet | Emily R Webb Georgia L Dodd Michaela Noskova Esme Bullock Morwenna Muir Margaret C Frame Alan Serrels Valerie G Brunton |
| author_sort | Emily R Webb |
| collection | DOAJ |
| description | The adhesion protein Kindlin-1 is over-expressed in breast cancer where it is associated with metastasis-free survival; however, the mechanisms involved are poorly understood. Here, we report that Kindlin-1 promotes anti-tumor immune evasion in mouse models of breast cancer. Deletion of Kindlin-1 in Met-1 mammary tumor cells led to tumor regression following injection into immunocompetent hosts. This was associated with a reduction in tumor infiltrating Tregs. Similar changes in T cell populations were seen following depletion of Kindlin-1 in the polyomavirus middle T antigen (PyV MT)-driven mouse model of spontaneous mammary tumorigenesis. There was a significant increase in IL-6 secretion from Met-1 cells when Kindlin-1 was depleted and conditioned media from Kindlin-1-depleted cells led to a decrease in the ability of Tregs to suppress the proliferation of CD8+ T cells, which was dependent on IL-6. In addition, deletion of tumor-derived IL-6 in the Kindlin-1-depleted tumors reversed the reduction of tumor-infiltrating Tregs. Overall, these data identify a novel function for Kindlin-1 in regulation of anti-tumor immunity, and that Kindlin-1 dependent cytokine secretion can impact the tumor immune environment. |
| first_indexed | 2024-04-09T23:49:33Z |
| format | Article |
| id | doaj.art-c3ca53b8a4394469ab79acf4dee4d370 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T23:49:33Z |
| publishDate | 2023-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c3ca53b8a4394469ab79acf4dee4d3702023-03-17T15:12:42ZengeLife Sciences Publications LtdeLife2050-084X2023-03-011210.7554/eLife.85739Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer modelsEmily R Webb0https://orcid.org/0000-0001-9339-4544Georgia L Dodd1Michaela Noskova2Esme Bullock3Morwenna Muir4Margaret C Frame5https://orcid.org/0000-0001-5882-1942Alan Serrels6https://orcid.org/0000-0003-4992-6077Valerie G Brunton7https://orcid.org/0000-0002-7778-8794Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomThe adhesion protein Kindlin-1 is over-expressed in breast cancer where it is associated with metastasis-free survival; however, the mechanisms involved are poorly understood. Here, we report that Kindlin-1 promotes anti-tumor immune evasion in mouse models of breast cancer. Deletion of Kindlin-1 in Met-1 mammary tumor cells led to tumor regression following injection into immunocompetent hosts. This was associated with a reduction in tumor infiltrating Tregs. Similar changes in T cell populations were seen following depletion of Kindlin-1 in the polyomavirus middle T antigen (PyV MT)-driven mouse model of spontaneous mammary tumorigenesis. There was a significant increase in IL-6 secretion from Met-1 cells when Kindlin-1 was depleted and conditioned media from Kindlin-1-depleted cells led to a decrease in the ability of Tregs to suppress the proliferation of CD8+ T cells, which was dependent on IL-6. In addition, deletion of tumor-derived IL-6 in the Kindlin-1-depleted tumors reversed the reduction of tumor-infiltrating Tregs. Overall, these data identify a novel function for Kindlin-1 in regulation of anti-tumor immunity, and that Kindlin-1 dependent cytokine secretion can impact the tumor immune environment.https://elifesciences.org/articles/85739T cellsIL6anti-tumor immunity |
| spellingShingle | Emily R Webb Georgia L Dodd Michaela Noskova Esme Bullock Morwenna Muir Margaret C Frame Alan Serrels Valerie G Brunton Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models eLife T cells IL6 anti-tumor immunity |
| title | Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models |
| title_full | Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models |
| title_fullStr | Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models |
| title_full_unstemmed | Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models |
| title_short | Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models |
| title_sort | kindlin 1 regulates il 6 secretion and modulates the immune environment in breast cancer models |
| topic | T cells IL6 anti-tumor immunity |
| url | https://elifesciences.org/articles/85739 |
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