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

Publication ,  Journal Article
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 in: Cancer research
January 2016

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.

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Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

January 2016

Volume

76

Issue

2

Start / End Page

227 / 238

Related Subject Headings

  • Transfection
  • TOR Serine-Threonine Kinases
  • Programmed Cell Death 1 Receptor
  • Oncology & Carcinogenesis
  • Oncogene Protein v-akt
  • Mice
  • Lung Neoplasms
  • Humans
  • Carcinoma, Non-Small-Cell Lung
  • Animals
 

Citation

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Lastwika, K. J., Wilson, W., Li, Q. K., Norris, J., Xu, H., Ghazarian, S. R., … Dennis, P. A. (2016). Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer Research, 76(2), 227–238. https://doi.org/10.1158/0008-5472.can-14-3362
Lastwika, Kristin J., Willie Wilson, Qing Kay Li, Jeffrey Norris, Haiying Xu, Sharon R. Ghazarian, Hiroshi Kitagawa, et al. “Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.Cancer Research 76, no. 2 (January 2016): 227–38. https://doi.org/10.1158/0008-5472.can-14-3362.
Lastwika KJ, Wilson W, Li QK, Norris J, Xu H, Ghazarian SR, et al. Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer research. 2016 Jan;76(2):227–38.
Lastwika, Kristin J., et al. “Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.Cancer Research, vol. 76, no. 2, Jan. 2016, pp. 227–38. Epmc, doi:10.1158/0008-5472.can-14-3362.
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. Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer research. 2016 Jan;76(2):227–238.

Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

January 2016

Volume

76

Issue

2

Start / End Page

227 / 238

Related Subject Headings

  • Transfection
  • TOR Serine-Threonine Kinases
  • Programmed Cell Death 1 Receptor
  • Oncology & Carcinogenesis
  • Oncogene Protein v-akt
  • Mice
  • Lung Neoplasms
  • Humans
  • Carcinoma, Non-Small-Cell Lung
  • Animals