miRNome functional profiling of non-small cell lung cancer identified new mechanisms of PD-L1 regulation

The use of immune checkpoint blockade (ICI), such as anti-PD-(L)-1 antibodies, has emerged as an effective treatment for both locally-advanced and advanced NSCLC. PD-L1 expression in cancer cells is regulated by a plethora of genetic and epigenetic mechanisms including genomic alterations, aberrant oncogenic and inflammatory pathways, post-transcriptional regulators (e.g., miRNA) and post-translational modification (e.g., ubiquitination, phosphorylation, glycosylation, palmitoylation). All these molecular processes contribute to dynamic and spatially heterogenous PD-L1 expression profile in lung cancer samples, which complicates PD-L1 pathological assessment thus limiting diagnostic accuracy. Interestingly, the 3’ UTR of PD-L1 gene is disrupted in several tumor types, leading to a stabilized form of PD-L1 and high expression (i.e., with TPS≥ 50%). The 3’ UTR of genes can be bound by microRNAs, small non-coding RNA that function as post- transcriptional regulators of gene expression, which induce mRNA degradation and translational repression.