The role of pi3k-akt-mtor signaling pathway on pd- 1/pd-l1 expression in cancers

The PI3K-AKT-mTOR signaling network is hyperactivated in many cancer types and controls most hallmarks of cancer including cell cycle, survival, metabolism, motility and genomic instability. Thus,targeting of this pathway was seen as an opportunity to overcome tumor complexity. In addition to this pathway, clinical success of cancer immunotherapies targeting the checkpoint receptors PD-1 and itsligands (PD-L1 and PD-L2) has proved the importance of immune evasion as a hallmark of cancer. Interestingly, pharmacological inhibition of the PI3K-AKT-mTOR pathway has been demonstrated to reduce the expression of PD-L1. In line with this findings, immunosuppressive cytokines secreted from tumors as a result of PI3K-AKT-mTOR pathway can inhibit tumor-specific CD8+ T cell activity. Furthermore, a variety of human tumors lacking expression of Phosphatase and Tensin homolog (PTEN), a negative regulator of PI3K pathway, have been shown to constitutively express PD-L1. By contrast, melanoma cells containing wild-type PTEN, cultured in the presence of a PI3K and mTOR inhibitors, failed to attenuate PD-L1 expression level. Thus, PI3K-AKT-mTOR signaling pathway inhibitors can have dichotomous functions; they can inhibit tumor cell proliferation, and augment tumor immune surveillance. Look forward, an increased knowledge of the immuno-modulatory effects of PI3K-AKT-mTOR inhibitors may allow its rationale combination with other therapies to improve clinical outcomes for patients although safety of each combination will have to be thoroughly assessed

کلیدواژه ها:

Cell and Cancer ، Cancer Risks ، Cancer Genetics ، Solid Tumors ، Cancer Treatment and Management