Regulation and Consequences of PD-L1 Expression in Non-Small Cell Lung Cancer Open Access
Activation of PI3K/AKT/mTOR signaling is commonly found in NSCLC through multiple mechanisms and is vital to tumor development, progression and prognosis. Here we tested the hypothesis that expression of the immunosuppressive protein PD-L1 is driven by activation of the AKT/mTOR pathway in lung cancer. We show that activation of AKT/mTOR through oncogenes, loss of tumor suppressors, or exogenous stimuli increases PD-L1 protein expression in NSCLC. PD-L1 plays an important role in lung tumorigenesis as knockdown of PD-L1 in the tumor alone or paired with loss of PD-L1 in the microenvironment hindered tumor growth in a syngeneic model of lung cancer. In the transgenic KRAS LA2 mouse model, lung tumorigenesis was reduced only when both PD-L1 and its receptor PD-1 were inhibited via genetic loss and a blocking antibody, respectively. Alternatively, combining rapamycin, an mTOR inhibitor which also decreases PD-L1 expression, with a PD-1 blocking antibody significantly reduced tumor burden by approximately 77% in both syngeneic and transgenic mouse models of KRAS-driven lung cancer. This reduction in tumorigenesis was associated with an increase in activated T cells and a decrease in Tregs, along with an increase in the apoptosis marker cleaved caspase 3, a decrease in the proliferation marker Ki67, and an increase in the epigenetic marker of senescence pHP1-gamma. These data extend a growing body of evidence that oncogenes have extrinsic effects by influencing anti-tumor immunity.
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