Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer

Kristin J. Lastwika, Willie Wilson, Qing Kay Li, Jeffrey Norris, Haiying Xu, Sharon R. Ghazarian, Hiroshi Kitagawa, Shigeru Kawabata, Janis M. Taube, Sheng Yao, Linda N. Liu, Joell J. Gills, Phillip A. Dennis

Research output: Contribution to journalArticlepeer-review

Abstract

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 anmTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.

Original languageEnglish (US)
Pages (from-to)227-238
Number of pages12
JournalCancer Research
Volume76
Issue number2
DOIs
StatePublished - Jan 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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