Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lastwika, KJ; Wilson, W; Li, QK; Norris, J; Xu, H; Ghazarian, SR; Kitagawa, H; Kawabata, S; Taube, JM; Yao, S; Liu, LN; Gills, JJ; Dennis, PA

Published Date

  • January 15, 2016

Published In

Volume / Issue

  • 76 / 2

Start / End Page

  • 227 - 238

PubMed ID

  • 26637667

Electronic International Standard Serial Number (EISSN)

  • 1538-7445

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-14-3362

Language

  • eng

Conference Location

  • United States