PD-L1 genomic abnormalities and its potential as a biomarker.

Abstract

PD-1/PD-L1 immune checkpoint pathway, which maintains self-tolerance and limits collateral tissue damage in a physiological state, can be co-opted by cancer cells to evade immune surveillance. Immune checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1 antibodies, can unleash anti-tumor immunity and mediate durable cancer regression. However, the complex biology of this pathway has not been fully elucidated, including the genetic basis of PD-L1 upregulation in cancer. Recently, we have identified a novel genetic mechanism of immune evasion associated with structural variations (SVs) disrupting the 3’-untranlated region (UTR) of the PD-L1 gene in a variety of cancers. Despite a large diversity in SV type, these SVs are invariably associated with a marked increase of PD-L1 expression, which promotes tumor progression and immune escape. Here we present an overview of PD-1/PD-L1 immune checkpoint blockade therapy, and highlight the genetic mechanisms of PD-L1 activation, including copy number amplification, promoter replacement, as well as 3’-UTR disruption, with a special focus on their relevance as a biomarker.