Universität zu Köln

Selenz, Carolin, Compes, Anik, Nill, Marieke, Borchmann, Sven, Odenthal, Margarete ORCID: 0000-0002-2424-0960, Florin, Alexandra, Braegelmann, Johannes, Buettner, Reinhard, Meder, Lydia and Ullrich, Roland T. (2022). EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer. Cancers, 14 (16). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary Lung cancer that is driven by mutations in the epidermal growth factor receptor (EGFR) is currently treated with tyrosine kinase inhibitors (TKIs). Although patients initially respond well to TKI treatment, drug resistance against EGFR-targeted therapy emerges. Attempts to combine immunotherapy with EGFR-targeted treatment to prolong response rates or prevent the development of resistances have been limited due to insufficient knowledge about the effects of targeted therapy on the tumour microenvironment (TME) in EGFR-driven tumours and tumour-infiltrating immune cells. The aims of this study were to improve our understanding on the impact of EGFR inhibition on the immune response in EGFR-driven lung cancer and, furthermore, to gain insights into the impact of combining targeted therapy with immunotherapy on the TME. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Selenz, Carolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Compes, Anik UNSPECIFIED UNSPECIFIED UNSPECIFIED Nill, Marieke UNSPECIFIED UNSPECIFIED UNSPECIFIED Borchmann, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED orcid.org/0000-0002-2424-0960 UNSPECIFIED Florin, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Braegelmann, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Meder, Lydia UNSPECIFIED UNSPECIFIED UNSPECIFIED Ullrich, Roland T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-658337
DOI:	10.3390/cancers14163943
Journal or Publication Title:	Cancers
Volume:	14
Number:	16
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TYROSINE KINASE INHIBITOR; CHECKPOINT INHIBITORS; DOWN-REGULATION; T-CELLS; ACTIVATION; PD-L1; STATISTICS; RESISTANCE; RECEPTORS; SURVIVAL Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/65833