Treatment with inhibition of programmed cell death 1 (PD-1) or its
ligand (PD-L1) improves survival in advanced
non-small-cell lung cancer (NSCLC). Nevertheless, only a subset of patients benefit from treatment and
biomarkers of response to
immunotherapy are lacking. Expression of PD-L1 on
tumor cells is the primary clinically-available predictive factor of response to
immune checkpoint inhibitors, and its relevance in
cancer immunotherapy has fostered several studies to better characterize the mechanisms that regulate PD-L1 expression. However, the factors associated with PD-L1 expression are still not well understood. Genomic alterations that activate KRAS, EGFR, and ALK, as well as the loss of PTEN, have been associated with increased PD-L1 expression. In addition, PD-L1 expression is reported to be increased by amplification of CD274, and decreased by STK11 deficiency. Furthermore, PD-L1 expression can be modulated by either
tumor extrinsic or intrinsic factors. Among extrinsic factors, the most prominent one is
interferon-γ release by immune cells, while there are several
tumor intrinsic factors such as activation of the mechanistic target of
rapamycin (mTOR),
mitogen-activated protein kinase (MAPK) and Myc pathways that can increase PD-L1 expression. A deeper understanding of PD-L1 expression regulation is crucial for improving strategies that exploit inhibition of this immune checkpoint in the clinic, especially in NSCLC where it is central in the therapeutic algorithm. We reviewed current preclinical and clinical data about PD-L1 expression regulation in NSCLC.