Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
| Autor: | Glenn Dranoff, Gordon J. Freeman, Margaret Soucheray, Camilla L. Christensen, Matthew D. Wilkerson, Mohit Butaney, Lynette M. Sholl, Andrew D. Cherniack, Esra A. Akbay, D. Neil Hayes, Travis J. Cohoon, Kwok-Kin Wong, Shohei Koyama, Julian Carretero, Oliver Mikse, Peter S. Hammerman, Scott J. Rodig, Jeremy H. Tchaicha, Peter E. Fecci, Jacob B. Reibel, Pasi A. Jänne, Geoffrey I. Shapiro, Matthew Meyerson, Ellen M. Beauchamp, Abigail Altabef, Takeshi Shimamura, Trevor J. Pugh |
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| Rok vydání: | 2013 |
| Předmět: |
Lung Neoplasms
T-Lymphocytes T cell Programmed Cell Death 1 Receptor Mice Transgenic Lymphocyte Activation B7-H1 Antigen Article Cell Line Proinflammatory cytokine Mice Carcinoma Non-Small-Cell Lung Tumor Microenvironment medicine Animals Humans Cytotoxic T cell Epidermal growth factor receptor Lung cancer EGFR inhibitors Tumor microenvironment biology Oncogenes medicine.disease ErbB Receptors Gene Expression Regulation Neoplastic Mice Inbred C57BL medicine.anatomical_structure Oncology Tumor Escape Immunology Cancer research biology.protein Cytokines Signal Transduction |
| Zdroj: | Cancer Discovery. 3:1355-1363 |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-13-0310 |
| Popis: | 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. Cancer Discov; 3(12); 1355–63. ©2013 AACR. See related commentary by Rech and Vonderheide, p. 1330 This article is highlighted in the In This Issue feature, p. 1317 |
| Databáze: | OpenAIRE |
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