The Mechanisms of PD-L1 Regulation in Non-Small-Cell Lung Cancer (NSCLC): Which Are the Involved Players?

SIMPLE SUMMARY: Immunotherapy against PD-1/PD-L1 dramatically improved outcomes in non-small cell lung cancer patients. These treatments are more effective the higher the expression of PD-L1 on tumor cells, reported as tumor proportion score. However, PD-L1 expression can be highly variable, depending on different mechanisms of regulation. These mechanisms are usually grouped in intrisc (including genetic and epigenetic factors) and extrinsic factors (i.e., deriving from interaction of tumor cells with tumor microenvironment or other external factors). We reviewed mechanisms underlying PD-L1 expression regulation in order to provide a comprehensive overview and identify key regulatory factors that are or can potentially be exploited to improve outcomes on immune checkpoint inhibitors targeting the PD-1/PD-L1 axis. ABSTRACT: 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.