Abstract 4981: PI3K/AKT/mTOR pathway activation drives expression of the immune inhibitory ligand PD-L1 in NSCLC.

Abstract

Abstract Despite the development of targeted drug therapies, lung cancer remains the leading cause of cancer-related death worldwide. Targeting immune checkpoints altered in cancer, such as the T cell inhibitory receptors programmed death 1 (PD-1) or CTLA4, represent promising new approaches to lung cancer treatment. Here we investigated the relationship of activation of the PI3K/Akt/mTOR signaling pathway and expression of the immune suppressive ligand, PD-L1, in non-small cell lung cancer (NSCLC). NSCLC cell lines with mutations in KRas, EGFR, BRaf, ALK or RET had high levels of PI3K/Akt/mTOR pathway activation as well as increased expression of PD-L1. Cell lines that lacked these mutations had low PI3K/Akt/mTOR pathway activation and less PD-L1 expression. In murine cell lines derived from tobacco carcinogen (NNK)-induced lung tumors, high levels of active Akt correlated with high PD-L1 expression. Agonists of the PI3K/Akt/mTOR pathway activation such as EGF or the carcinogen NNK, as well as knockdown of PTEN or induction of Kras induced PD-L1 expression. Conversely, treatment of high PD-L1 expressing NSCLC cell lines with inhibitors of PI3K (LY294002), AKT (triciribine) or mTOR (rapamycin) decreased PD-L1 expression. These inhibitors decreased PD-L1 protein levels, but did not alter PD-L1 mRNA. Rapamycin-mediated PD-L1 loss was partially blocked by pre-treatment with a lysosomal, but not a proteosomal inhibitor. In vivo, increased expression of PD-L1 and activation of mTOR was an early event after exposure to NNK and was blocked by rapamycin. To test the efficacy of blocking PD-1 while reducing the expression of PD-L1 in tumor tissue, rapamycin and a murine anti-PD-1 receptor antibody were administered to A/J mice bearing syngeneic lung tumor xenografts. The combination decreased the tumor growth rate to a greater degree than either agent alone and decreased mTOR pathway signaling, PD-L1 expression, and increased cleaved caspase 3. Tumor associated activated CD8+ T cells were also increased in the tumors. These data support a relationship between activation of PI3K/Akt/mTOR signaling, PD-L1 expression and the development of an immune resistant phenotype in lung cancer. Combination regimens using PI3K/Akt/mTOR inhibitors may enhance the efficacy of immune therapies targeting PD-1. Citation Format: Kristin Lastwika, Willie Wilson, Phillip A. Dennis. PI3K/AKT/mTOR pathway activation drives expression of the immune inhibitory ligand PD-L1 in NSCLC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4981. doi:10.1158/1538-7445.AM2013-4981