Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
The discovery of immune checkpoints has been well known to provide novel clues for cancer treatments. Immunotherapy against the programmed cell death protein-1 (PD-1) /programmed death-ligand-1 (PD-L1), one of the most popular auxiliary treatments in recent years, has been applied in various tumor treatments, including non-small cell lung cancer (NSCLC). However, inevitable issues such as side effects and drug resistance emerge following the use of immune checkpoint inhibitors. The PI3K/AKT/mTOR pathway may participate in the regulation of PD-L1 expression. Abnormal PI3K/AKT/mTOR pathway activation results in increased PD-L1 protein translation, whereas PD-L1 overexpression can activate the PI3K/AKT/mTOR pathway inversely. Via downstream proteins, including 4E-BP1, STAT3, NF-κB, c-MYC, and AMPK in aberrant energy status, the PI3K/AKT/mTOR pathway can regulate PD-L1 post-transcription and translation. Besides, the regulation of the PI3K pathway by the PD-1/PD-L1 axis involves both tumor cells and the tumor immune microenvironment. Inhibitors targeting the PD-1/PD-L1 have been successfully applied in the treatment of gastrointestinal cancer and breast cancer. Meanwhile, drug resistance from alternative pathway activation also evidently affects clinical progress. To achieve a better therapeutic effect and quality of survival, the combination of multiple treatment modalities presents great research value. Here we reviewed the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in the progression and treatment of NSCLC and summarized its clinical implications. The intracellular interactions between PD-1/PD-L1 and the PI3K/AKT/mTOR pathway indicate that PD-1/PD-L1 inhibitors have a wide range of potential applications. And we presented the mechanism for combining therapy with monoclonal antibody PD-1/PD-L1 and PI3K/AKT/mTOR inhibitors in this review, to broaden the therapies for NSCLC.
Keywords: PD-1/PD-L1, PI3K/AKT/mTOR pathway, Inhibitors, immunotherapy