Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages
Objective: The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucid...
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China Anti-Cancer Association
2024-12-01
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| Series: | Cancer Biology & Medicine |
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| Online Access: | https://www.cancerbiomed.org/content/21/12/1156 |
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| author | Yuan Li Yanping Chen Yuan Meng Meng Shen Fan Yang Xiubao Ren |
| author_facet | Yuan Li Yanping Chen Yuan Meng Meng Shen Fan Yang Xiubao Ren |
| author_sort | Yuan Li |
| collection | DOAJ |
| description | Objective: The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. Methods: An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. Results: Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. Conclusions: An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines. |
| format | Article |
| id | doaj-art-201b5335a56642878ba275c0bbb14544 |
| institution | Kabale University |
| issn | 2095-3941 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj-art-201b5335a56642878ba275c0bbb145442025-02-05T09:57:37ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412024-12-0121121156117010.20892/j.issn.2095-3941.2024.0269Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophagesYuan Li0Yanping Chen1Yuan Meng2Meng Shen3Fan Yang4Xiubao Ren5Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, ChinaDepartment of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, ChinaDepartment of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, ChinaDepartment of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, ChinaDepartment of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, ChinaDepartment of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, ChinaObjective: The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. Methods: An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. Results: Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. Conclusions: An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines.https://www.cancerbiomed.org/content/21/12/1156osimertinibicisiraesmacrophagesil-6/jak/stat3 |
| spellingShingle | Yuan Li Yanping Chen Yuan Meng Meng Shen Fan Yang Xiubao Ren Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages Cancer Biology & Medicine osimertinib icis iraes macrophages il-6/jak/stat3 |
| title | Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages |
| title_full | Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages |
| title_fullStr | Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages |
| title_full_unstemmed | Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages |
| title_short | Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages |
| title_sort | osimertinib exacerbates immune checkpoint inhibitor related severe adverse events by activating the il 6 jak stat3 pathway in macrophages |
| topic | osimertinib icis iraes macrophages il-6/jak/stat3 |
| url | https://www.cancerbiomed.org/content/21/12/1156 |
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