Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.
By K. Lastwika, W. Wilson, Q. K. Li, J. Norris, Haiying Xu, S. Ghazarian, H. Kitagawa, S. Kawabata, Janis Taube, Sheng Yao and 3 more. Cancer Research, 2016
703 citations recorded by the source corpus.
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.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/d150eb0251a8a5d9f9890480e3416e884897f378
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Citations in the corpus
- Targeting PI3K/Akt signal transduction for cancer therapy (2021, background): “In mouse lung cancer models and human lung cancer cell lines, the Akt signaling pathway regulates the expression of PD-L1 at the protein translation level.(146) In conclusion, the PI3K/Akt signaling pathway is obviously related to immune resistance, which provides a basis for combined therapeutic st”
- PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer (2023, background): “In syngeneic and genet-ically-engineered mouse models of lung cancer, inhibition of mTOR bolsters the effects of PD-1 blockade [422].”
- The PI3K pathway in human disease (2017, positive): “PI3K/mTOR pathway activation in lung cancer models was associated with increased expression of the PD-1 ligand PD-L1, and combination therapy with rapamycin plus anti-PD1 antibody significantly reduced tumor burden in a KRAS -driven mouse NSCLC model (Lastwika et al., 2016).”