Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors
Abstract Background Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or dela...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0643-8 |
| _version_ | 1798043061335359488 |
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| author | Deborah Ayeni Braden Miller Alexandra Kuhlmann Ping-Chih Ho Camila Robles-Oteiza Mmaserame Gaefele Stellar Levy Fernando J. de Miguel Curtis Perry Tianxia Guan Gerald Krystal William Lockwood Daniel Zelterman Robert Homer Zongzhi Liu Susan Kaech Katerina Politi |
| author_facet | Deborah Ayeni Braden Miller Alexandra Kuhlmann Ping-Chih Ho Camila Robles-Oteiza Mmaserame Gaefele Stellar Levy Fernando J. de Miguel Curtis Perry Tianxia Guan Gerald Krystal William Lockwood Daniel Zelterman Robert Homer Zongzhi Liu Susan Kaech Katerina Politi |
| author_sort | Deborah Ayeni |
| collection | DOAJ |
| description | Abstract Background Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Methods Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment. Results We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs and increased maturation of alveolar macrophages. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. We also found that further efforts to boost the function and abundance of inflammatory cells, by combining erlotinib treatment with anti-PD-1 and/or a CD40 agonist, did not improve survival in an EGFR-driven mouse model. Conclusions Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlight the importance of investigating targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer. |
| first_indexed | 2024-04-11T22:44:21Z |
| format | Article |
| id | doaj.art-747919cbf484433eaa47ef5535f2fc44 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-11T22:44:21Z |
| publishDate | 2019-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-747919cbf484433eaa47ef5535f2fc442022-12-22T03:58:49ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-07-017111510.1186/s40425-019-0643-8Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumorsDeborah Ayeni0Braden Miller1Alexandra Kuhlmann2Ping-Chih Ho3Camila Robles-Oteiza4Mmaserame Gaefele5Stellar Levy6Fernando J. de Miguel7Curtis Perry8Tianxia Guan9Gerald Krystal10William Lockwood11Daniel Zelterman12Robert Homer13Zongzhi Liu14Susan Kaech15Katerina Politi16Department of Pathology, Yale School of MedicineYale Cancer Center, Yale School of MedicineDepartment of Immunobiology, Yale School of MedicineDepartment of Immunobiology, Yale School of MedicineDepartment of Immunobiology, Yale School of MedicineYale Cancer Center, Yale School of MedicineYale Cancer Center, Yale School of MedicineYale Cancer Center, Yale School of MedicineDepartment of Immunobiology, Yale School of MedicineDepartment of Immunobiology, Yale School of MedicineBritish Columbia Cancer AgencyBritish Columbia Cancer AgencyDepartment of Biostatistics, Yale School of Public HealthDepartment of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineYale Cancer Center, Yale School of MedicineDepartment of Pathology, Yale School of MedicineAbstract Background Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Methods Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment. Results We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs and increased maturation of alveolar macrophages. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. We also found that further efforts to boost the function and abundance of inflammatory cells, by combining erlotinib treatment with anti-PD-1 and/or a CD40 agonist, did not improve survival in an EGFR-driven mouse model. Conclusions Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlight the importance of investigating targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.http://link.springer.com/article/10.1186/s40425-019-0643-8Lung cancerEGFRTargeted therapiesImmunotherapiesMouse models |
| spellingShingle | Deborah Ayeni Braden Miller Alexandra Kuhlmann Ping-Chih Ho Camila Robles-Oteiza Mmaserame Gaefele Stellar Levy Fernando J. de Miguel Curtis Perry Tianxia Guan Gerald Krystal William Lockwood Daniel Zelterman Robert Homer Zongzhi Liu Susan Kaech Katerina Politi Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors Journal for ImmunoTherapy of Cancer Lung cancer EGFR Targeted therapies Immunotherapies Mouse models |
| title | Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors |
| title_full | Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors |
| title_fullStr | Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors |
| title_full_unstemmed | Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors |
| title_short | Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors |
| title_sort | tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in egfr mutant lung tumors |
| topic | Lung cancer EGFR Targeted therapies Immunotherapies Mouse models |
| url | http://link.springer.com/article/10.1186/s40425-019-0643-8 |
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