Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors

Esra A. Akbay, Shohei Koyama, Julian Carretero, Abigail Altabef, Jeremy H. Tchaicha, Camilla L. Christensen, Oliver R. Mikse, Andrew D. Cherniack, Ellen M. Beauchamp, Trevor J. Pugh, Matthew D. Wilkerson, Peter E. Fecci, Mohit Butaney, Jacob B. Reibel, Margaret Soucheray, Travis J. Cohoon, Pasi A. Janne, Matthew Meyerson, D. Neil Hayes, Geoffrey I. ShapiroTakeshi Shimamura, Lynette M. Sholl, Scott J. Rodig, Gordon J. Freeman, Peter S. Hammerman, Glenn Dranoff, Kwok Kin Wong

Research output: Contribution to journalArticle

566 Citations (Scopus)

Abstract

The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumorpromoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition. SIGNIFICANCE: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape.

Original languageEnglish (US)
Pages (from-to)1355-1363
Number of pages9
JournalCancer Discovery
Volume3
Issue number12
DOIs
StatePublished - Dec 1 2013

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Epidermal Growth Factor Receptor
Lung
Neoplasms
Cytokines
T-Lymphocytes
Oncogenes
Lung Neoplasms
Leukocyte L1 Antigen Complex
Tumor Microenvironment
Non-Small Cell Lung Carcinoma
Immunosuppression
Immunity
Adenocarcinoma
Up-Regulation
Epithelial Cells
Cell Line
Antibodies
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

Akbay, E. A., Koyama, S., Carretero, J., Altabef, A., Tchaicha, J. H., Christensen, C. L., ... Wong, K. K. (2013). Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discovery, 3(12), 1355-1363. https://doi.org/10.1158/2159-8290.CD-13-0310

Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. / Akbay, Esra A.; Koyama, Shohei; Carretero, Julian; Altabef, Abigail; Tchaicha, Jeremy H.; Christensen, Camilla L.; Mikse, Oliver R.; Cherniack, Andrew D.; Beauchamp, Ellen M.; Pugh, Trevor J.; Wilkerson, Matthew D.; Fecci, Peter E.; Butaney, Mohit; Reibel, Jacob B.; Soucheray, Margaret; Cohoon, Travis J.; Janne, Pasi A.; Meyerson, Matthew; Neil Hayes, D.; Shapiro, Geoffrey I.; Shimamura, Takeshi; Sholl, Lynette M.; Rodig, Scott J.; Freeman, Gordon J.; Hammerman, Peter S.; Dranoff, Glenn; Wong, Kwok Kin.

In: Cancer Discovery, Vol. 3, No. 12, 01.12.2013, p. 1355-1363.

Research output: Contribution to journalArticle

Akbay, EA, Koyama, S, Carretero, J, Altabef, A, Tchaicha, JH, Christensen, CL, Mikse, OR, Cherniack, AD, Beauchamp, EM, Pugh, TJ, Wilkerson, MD, Fecci, PE, Butaney, M, Reibel, JB, Soucheray, M, Cohoon, TJ, Janne, PA, Meyerson, M, Neil Hayes, D, Shapiro, GI, Shimamura, T, Sholl, LM, Rodig, SJ, Freeman, GJ, Hammerman, PS, Dranoff, G & Wong, KK 2013, 'Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors', Cancer Discovery, vol. 3, no. 12, pp. 1355-1363. https://doi.org/10.1158/2159-8290.CD-13-0310
Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discovery. 2013 Dec 1;3(12):1355-1363. https://doi.org/10.1158/2159-8290.CD-13-0310
Akbay, Esra A. ; Koyama, Shohei ; Carretero, Julian ; Altabef, Abigail ; Tchaicha, Jeremy H. ; Christensen, Camilla L. ; Mikse, Oliver R. ; Cherniack, Andrew D. ; Beauchamp, Ellen M. ; Pugh, Trevor J. ; Wilkerson, Matthew D. ; Fecci, Peter E. ; Butaney, Mohit ; Reibel, Jacob B. ; Soucheray, Margaret ; Cohoon, Travis J. ; Janne, Pasi A. ; Meyerson, Matthew ; Neil Hayes, D. ; Shapiro, Geoffrey I. ; Shimamura, Takeshi ; Sholl, Lynette M. ; Rodig, Scott J. ; Freeman, Gordon J. ; Hammerman, Peter S. ; Dranoff, Glenn ; Wong, Kwok Kin. / Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. In: Cancer Discovery. 2013 ; Vol. 3, No. 12. pp. 1355-1363.
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AU - Akbay, Esra A.

AU - Koyama, Shohei

AU - Carretero, Julian

AU - Altabef, Abigail

AU - Tchaicha, Jeremy H.

AU - Christensen, Camilla L.

AU - Mikse, Oliver R.

AU - Cherniack, Andrew D.

AU - Beauchamp, Ellen M.

AU - Pugh, Trevor J.

AU - Wilkerson, Matthew D.

AU - Fecci, Peter E.

AU - Butaney, Mohit

AU - Reibel, Jacob B.

AU - Soucheray, Margaret

AU - Cohoon, Travis J.

AU - Janne, Pasi A.

AU - Meyerson, Matthew

AU - Neil Hayes, D.

AU - Shapiro, Geoffrey I.

AU - Shimamura, Takeshi

AU - Sholl, Lynette M.

AU - Rodig, Scott J.

AU - Freeman, Gordon J.

AU - Hammerman, Peter S.

AU - Dranoff, Glenn

AU - Wong, Kwok Kin

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