Pan-Cancer Proteomic and Transcriptomic Meta-Analysis of PD-1/PD-L1 Signaling Reveals Predictive Biomarkers for Anti-PD‑1 Therapy in Lung Cancer

Programmed death-ligand 1 (PD-L1)
is an immune checkpoint
molecule
that enables tumor cells to escape immune surveillance, and its blockade
by immune checkpoint inhibitors has become an effective therapeutic
strategy in various cancers. Previous studies have primarily focused
on genomic and transcriptomic features within specific cancer types,
while proteomic analyses remain relatively limited. Here, we conducted
a comprehensive pan-cancer meta-analysis encompassing 12 human cancer
types to systematically characterize PD-1/PD-L1 signaling pathways
at both the proteomic and transcriptomic levels. We observed clear
cancer-type-specific patterns of PD-1/PD-L1 expression. Pathway-crosstalk
analyses further revealed multiple pathways and phosphorylation events
influencing PD-1/PD-L1 activity. Immune-infiltration profiling identified
MMP9+ neutrophils as key immune subsets associated with
PD-1/PD-L1 pathway activity. Using proteomic data, we constructed
a PD-L1-centered protein–protein interaction network and identified
TAP proteins as potential predictive biomarkers in small-cell lung
cancer. We also established a biomarker signature capable of predicting
clinical response to anti-PD-1 therapy in non-small-cell lung cancer
and validated this gene set in two independent previously published
cohorts. Finally, we developed an interactive web application (https://yuyingsuo-simm.shinyapps.io/PD-L1_Profiling/) to facilitate visualization of PD-L1 features and exploration of
its associations with genes and pathways of interest.