Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer
| Autor: | Kristin J. Lastwika, Hiroshi Kitagawa, Joell J. Gills, Willie Wilson, Jeffrey William Norris, Haiying Xu, Phillip A. Dennis, Sharon R. Ghazarian, Qing Kay Li, Sheng Yao, Janis M. Taube, Shigeru Kawabata, Linda N. Liu |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Programmed Cell Death 1 Receptor Cell AKT2 Biology Transfection medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine Immune system Carcinoma Non-Small-Cell Lung medicine Animals Humans Lung cancer Protein kinase B PI3K/AKT/mTOR pathway Tumor microenvironment TOR Serine-Threonine Kinases medicine.disease Cell biology Oncogene Protein v-akt 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research KRAS |
| Zdroj: | Cancer Research. 76:227-238 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-14-3362 |
| Popis: | Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT–mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT–mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells. Cancer Res; 76(2); 227–38. ©2015 AACR. |
| Databáze: | OpenAIRE |
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