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

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          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.

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          Author and article information

          Journal
          Cancer Discov
          Cancer discovery
          American Association for Cancer Research (AACR)
          2159-8290
          2159-8274
          Dec 2013
          : 3
          : 12
          Affiliations
          [1 ] Departments of 1Medicine and 2Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute; 3Harvard Medical School; 4Ludwig Institute for Cancer Research; 5Department of Neurosurgery, Massachusetts General Hospital; 6Belfer Institute for Applied Cancer Science; 7Department of Pathology, Brigham and Women's Hospital, Boston; 8Broad Institute, Cambridge, Massachusetts; 9UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and 10Department of Molecular Pharmacology and Therapeutics, Oncology Institute, Loyola University, Chicago, Illinois; 11Department of Physiology, University of Valencia, Valencia, Spain.
          Article
          2159-8290.CD-13-0310 NIHMS528785
          10.1158/2159-8290.CD-13-0310
          3864135
          24078774
          3254e86d-e3e2-4e61-85ab-f71e8a5d0f4e
          ©2013 AACR.
          History

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