Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors.
EGFR
Immunotherapies
Lung cancer
Mouse models
Targeted therapies
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
10 07 2019
10 07 2019
Historique:
received:
06
02
2019
accepted:
19
06
2019
entrez:
12
7
2019
pubmed:
12
7
2019
medline:
28
7
2020
Statut:
epublish
Résumé
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. Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31291990
doi: 10.1186/s40425-019-0643-8
pii: 10.1186/s40425-019-0643-8
pmc: PMC6617639
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Erlotinib Hydrochloride
DA87705X9K
EGFR protein, mouse
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
172Subventions
Organisme : NCI NIH HHS
ID : R01 CA195720
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA196530
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA193200
Pays : United States
Organisme : NCI NIH HHS
ID : F99 CA245819
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
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