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J Immunother Cancer. 2019 Jul 10;7(1):172. doi: 10.1186/s40425-019-0643-8.

Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors.

Author information

1
Department of Pathology, Yale School of Medicine, 333 Cedar Street, SHM-I 234D, New Haven, CT, 06510, USA.
2
Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06510, USA.
3
Department of Immunobiology, Yale School of Medicine, New Haven, CT, 06510, USA.
4
Present address: Department of Fundamental Oncology, University of Lausanne, Ludwig Cancer Research Lausanne Branch, Lausanne, Switzerland.
5
British Columbia Cancer Agency, B.C, Vancouver, V5Z 1L3, Canada.
6
Department of Biostatistics, Yale School of Public Health, New Haven, CT, 06510, USA.
7
VA Connecticut Healthcare System, Pathology and Laboratory Medicine Service, 950 Campbell Ave, West Haven, CT, 06516, USA.
8
Present address: Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
9
Department of Pathology, Yale School of Medicine, 333 Cedar Street, SHM-I 234D, New Haven, CT, 06510, USA. katerina.politi@yale.edu.
10
Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06510, USA. katerina.politi@yale.edu.
11
Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, CT, 06510, USA. katerina.politi@yale.edu.

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.

KEYWORDS:

EGFR; Immunotherapies; Lung cancer; Mouse models; Targeted therapies

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