title: Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.
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 an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland. The George Washington University, Institute for Biomedical Sciences, Washington, DC.
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Lastwika
authors.affiliation: Cancer Biology and Genetics Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Willie
authors.initials: W
authors.lastname: Wilson
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Qing Kay
authors.initials: QK
authors.lastname: Li
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Norris
authors.affiliation: Department of Dermatology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Haiying
authors.initials: H
authors.lastname: Xu
authors.affiliation: Biostatistics, Epidemiology and Data Management Core, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Ghazarian
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitagawa
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawabata
authors.affiliation: Department of Dermatology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
authors.affiliation: Amplimmune, Inc., Gaithersburg, Maryland.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yao
authors.affiliation: Amplimmune, Inc., Gaithersburg, Maryland.
authors.forename: Linda N
authors.initials: LN
authors.lastname: Liu
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Joell J
authors.initials: JJ
authors.lastname: Gills
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland. pdennis@jhmi.edu.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection
chemical_list: D061026:Programmed Cell Death 1 Receptor; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases