EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer
EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of i...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/16/3943 |
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| author | Carolin Selenz Anik Compes Marieke Nill Sven Borchmann Margarete Odenthal Alexandra Florin Johannes Brägelmann Reinhard Büttner Lydia Meder Roland T. Ullrich |
| author_facet | Carolin Selenz Anik Compes Marieke Nill Sven Borchmann Margarete Odenthal Alexandra Florin Johannes Brägelmann Reinhard Büttner Lydia Meder Roland T. Ullrich |
| author_sort | Carolin Selenz |
| collection | DOAJ |
| description | EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC. |
| first_indexed | 2024-03-09T04:38:26Z |
| format | Article |
| id | doaj.art-c2fc23d1318c4a28a3a560dc4d029809 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T04:38:26Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c2fc23d1318c4a28a3a560dc4d0298092023-12-03T13:25:04ZengMDPI AGCancers2072-66942022-08-011416394310.3390/cancers14163943EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung CancerCarolin Selenz0Anik Compes1Marieke Nill2Sven Borchmann3Margarete Odenthal4Alexandra Florin5Johannes Brägelmann6Reinhard Büttner7Lydia Meder8Roland T. Ullrich9Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyDepartment I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyDepartment I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyDepartment I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyInstitute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyInstitute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyInstitute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyDepartment I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyDepartment I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyEGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC.https://www.mdpi.com/2072-6694/14/16/3943NSCLCEGFRtyrosine kinase inhibitorsimmune checkpoint blockadeanti-PD-1erlotinib |
| spellingShingle | Carolin Selenz Anik Compes Marieke Nill Sven Borchmann Margarete Odenthal Alexandra Florin Johannes Brägelmann Reinhard Büttner Lydia Meder Roland T. Ullrich EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer Cancers NSCLC EGFR tyrosine kinase inhibitors immune checkpoint blockade anti-PD-1 erlotinib |
| title | EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer |
| title_full | EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer |
| title_fullStr | EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer |
| title_full_unstemmed | EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer |
| title_short | EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer |
| title_sort | egfr inhibition strongly modulates the tumour immune microenvironment in egfr driven non small cell lung cancer |
| topic | NSCLC EGFR tyrosine kinase inhibitors immune checkpoint blockade anti-PD-1 erlotinib |
| url | https://www.mdpi.com/2072-6694/14/16/3943 |
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