p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition
M2 macrophages promote tumor progression and therapy resistance, whereas proimmunogenic M1 macrophages can contribute to the efficacy of cytostatic and immunotherapeutic strategies. The abundance of M2 macrophages in the immune infiltrate of many cancer types has prompted the search for strategies t...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2021-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/7/e002319.full |
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| author | Rienk Offringa Daniel Baumann Jennifer Drebant Tanja Hägele Luisa Burger Clara Serger Claudia Lauenstein Przemyslaw Dudys Gerrit Erdmann |
| author_facet | Rienk Offringa Daniel Baumann Jennifer Drebant Tanja Hägele Luisa Burger Clara Serger Claudia Lauenstein Przemyslaw Dudys Gerrit Erdmann |
| author_sort | Rienk Offringa |
| collection | DOAJ |
| description | M2 macrophages promote tumor progression and therapy resistance, whereas proimmunogenic M1 macrophages can contribute to the efficacy of cytostatic and immunotherapeutic strategies. The abundance of M2 macrophages in the immune infiltrate of many cancer types has prompted the search for strategies to target and eliminate this subset. From our prior experiments in syngeneic mouse tumor models, we learned that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) did not merely result in tumor cell death, but also in the modulation of the tumor immune infiltrate. This included a prominent decrease in the numbers of macrophages as well as an increase in the M1/M2 macrophage ratio. Investigation of the mechanism underlying this finding in primary murine macrophage cultures revealed that M2 macrophages are significantly more sensitive to MEK inhibition-induced cell death than their M1 counterparts. Further analyses showed that the p38 MAPK pathway, which is activated in M1 macrophages only, renders these cells resistant to death by MEK inhibition. In conclusion, the dependency of M2 macrophages on the MEK/extracellular-signal regulated kinase (ERK) pathway empowers MEK inhibitors to selectively eliminate this subset from the tumor microenvironment. |
| format | Article |
| id | doaj-art-e263dc40a6cf4e1ea2e621b7d9a66997 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e263dc40a6cf4e1ea2e621b7d9a669972025-08-20T02:12:45ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-07-019710.1136/jitc-2020-002319p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibitionRienk Offringa0Daniel Baumann1Jennifer Drebant2Tanja Hägele3Luisa Burger4Clara Serger5Claudia Lauenstein6Przemyslaw Dudys7Gerrit Erdmann8DKFZ-Bayer Joint Immunotherapy Laboratory (D220), DKFZ-Bayer Joint Immunotherapy Laboratory, Heidelberg, GermanyDKFZ-Bayer Joint Immunotherapy Laboratory (D220), DKFZ-Bayer Joint Immunotherapy Laboratory, Heidelberg, GermanyDivision of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Baden-Württemberg, GermanyDivision of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Baden-Württemberg, GermanyDivision of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Baden-Württemberg, GermanyDivision of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Baden-Württemberg, GermanyDivision of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Baden-Württemberg, GermanyNMI TT Pharmaservices, Berlin, GermanyNMI TT Pharmaservices, Berlin, GermanyM2 macrophages promote tumor progression and therapy resistance, whereas proimmunogenic M1 macrophages can contribute to the efficacy of cytostatic and immunotherapeutic strategies. The abundance of M2 macrophages in the immune infiltrate of many cancer types has prompted the search for strategies to target and eliminate this subset. From our prior experiments in syngeneic mouse tumor models, we learned that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) did not merely result in tumor cell death, but also in the modulation of the tumor immune infiltrate. This included a prominent decrease in the numbers of macrophages as well as an increase in the M1/M2 macrophage ratio. Investigation of the mechanism underlying this finding in primary murine macrophage cultures revealed that M2 macrophages are significantly more sensitive to MEK inhibition-induced cell death than their M1 counterparts. Further analyses showed that the p38 MAPK pathway, which is activated in M1 macrophages only, renders these cells resistant to death by MEK inhibition. In conclusion, the dependency of M2 macrophages on the MEK/extracellular-signal regulated kinase (ERK) pathway empowers MEK inhibitors to selectively eliminate this subset from the tumor microenvironment.https://jitc.bmj.com/content/9/7/e002319.full |
| spellingShingle | Rienk Offringa Daniel Baumann Jennifer Drebant Tanja Hägele Luisa Burger Clara Serger Claudia Lauenstein Przemyslaw Dudys Gerrit Erdmann p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition Journal for ImmunoTherapy of Cancer |
| title | p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition |
| title_full | p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition |
| title_fullStr | p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition |
| title_full_unstemmed | p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition |
| title_short | p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition |
| title_sort | p38 mapk signaling in m1 macrophages results in selective elimination of m2 macrophages by mek inhibition |
| url | https://jitc.bmj.com/content/9/7/e002319.full |
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