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

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Authors: Akbay, E. A.; Koyama, S.; Carretero, J; Altabef, A.; Tchaicha, J. H.; Christensen, C. L.; Mikse, O. R.; Cherniack, A. D.; Beauchamp, E. M.; Pugh, T. J.; Wilkerson, M. D.; Fecci, P. E.; Butaney, M.; Reibel, J. B.; Soucheray, M; Cohoon, T. J.; Janne, P. A.; Meyerson, M.; Hayes, D. N.; Shapiro, G. I.; Shimamura, T; Sholl, L. M.; Rodig, S. J.; Freeman, G. J.; Hammerman, P. S.; Dranoff, G.; Wong, K. K.
Article Title: Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors
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 tumor-promoting 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.
Journal Title: Cancer discovery
Volume: 3
Issue: 12
ISSN: 2159-8290; 2159-8274
Publisher: AACR  
Journal Place: United States
Date Published: 2013
Start Page: 1355
End Page: 1363
Language: eng
DOI/URL:

10.1158/2159-8290.CD-13-0310
Notes: LR: 20150820; CI: (c)2013; GR: 1K08CA163677/CA/NCI NIH HHS/United States; GR: CA122794/CA/NCI NIH HHS/United States; GR: CA140594/CA/NCI NIH HHS/United States; GR: CA154303/CA/NCI NIH HHS/United States; GR: CA163896/CA/NCI NIH HHS/United States; GR: CA166480/CA/NCI NIH HHS/United States; GR: K08 CA163677/CA/NCI NIH HHS/United States; GR: P01 CA078378/CA/NCI NIH HHS/United States; GR: P01 CA154303/CA/NCI NIH HHS/United States; GR: P01 CA155258/CA/NCI NIH HHS/United States; GR: P50 CA090578/CA/NCI NIH HHS/United States; GR: P50 CA100707/CA/NCI NIH HHS/United States; GR: P50CA090578/CA/NCI NIH HHS/United States; GR: R01 CA116020/CA/NCI NIH HHS/United States; GR: R01 CA122794/CA/NCI NIH HHS/United States; GR: R01 CA140594/CA/NCI NIH HHS/United States; GR: R01 CA143083/CA/NCI NIH HHS/United States; GR: R01 CA163896/CA/NCI NIH HHS/United States; GR: R01 CA166480/CA/NCI NIH HHS/United States; GR: R01CA143083/CA/NCI NIH HHS/United States; GR: U54CA163125/CA/NCI NIH HHS/United States; JID: 101561693; 0 (Antigens, CD274); 0 (Cytokines); 0 (Programmed Cell Death 1 Receptor); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); CIN: Cancer Discov. 2013 Dec;3(12):1330-2. PMID: 24327693; NIHMS528785; OID: NLM: NIHMS528785; OID: NLM: PMC3864135; 2013/09/27 [aheadofprint]; 2013/11/22 [aheadofprint]; ppublish