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

Deborah Ayeni, Braden Miller, Alexandra Kuhlman, Ping-Chih Ho, Camila Robles-Oteiza, Mmaserame Gaefele, Stellar Levy, Fernando J. de Miguel, Curtis Perry, Tianxia Guan, Daniel Zelterman, Robert Homer, Zongzhi Liu, Susan Kaech, Katerina Politi
doi: https://doi.org/10.1101/254847
Deborah Ayeni
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
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Braden Miller
2Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510
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Alexandra Kuhlman
3Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
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Ping-Chih Ho
3Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
4Present address: Department of Fundamental Oncology, University of Lausanne, Switzerland. Ludwig Cancer Research Lausanne Branch
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Camila Robles-Oteiza
3Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
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Mmaserame Gaefele
2Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510
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Stellar Levy
2Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510
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Fernando J. de Miguel
2Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510
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Curtis Perry
3Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
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Tianxia Guan
3Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
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Daniel Zelterman
5Department of Biostatistics, Yale University School of Public Health, New Haven, CT 06510
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Robert Homer
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
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Zongzhi Liu
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
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Susan Kaech
2Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510
3Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
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Katerina Politi
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
2Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510
6Department of Medicine (Section of Medical Oncology), Yale University School of Medicine, New Haven, CT 06510
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  • For correspondence: katerina.politi@yale.edu
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Abstract

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. 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. Erlotinib treatment also led to increased maturation of myeloid cells and an increase in CD40+ dendritic cells. Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlights potential avenues for investigation of targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.

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Posted January 27, 2018.
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Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors
Deborah Ayeni, Braden Miller, Alexandra Kuhlman, Ping-Chih Ho, Camila Robles-Oteiza, Mmaserame Gaefele, Stellar Levy, Fernando J. de Miguel, Curtis Perry, Tianxia Guan, Daniel Zelterman, Robert Homer, Zongzhi Liu, Susan Kaech, Katerina Politi
bioRxiv 254847; doi: https://doi.org/10.1101/254847
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Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors
Deborah Ayeni, Braden Miller, Alexandra Kuhlman, Ping-Chih Ho, Camila Robles-Oteiza, Mmaserame Gaefele, Stellar Levy, Fernando J. de Miguel, Curtis Perry, Tianxia Guan, Daniel Zelterman, Robert Homer, Zongzhi Liu, Susan Kaech, Katerina Politi
bioRxiv 254847; doi: https://doi.org/10.1101/254847

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