Pan-Cancer Proteomics Analysis Reveals Wiskott–Aldrich Syndrome Protein as a Potential Regulator of Programmed Death-Ligand 1

The
programmed death-ligand 1 (PD-L1) is a key mediator of immunosuppression
in the tumor microenvironment. The expression of PD-L1 in cancer cells
is useful for the clinical determination of an immune checkpoint blockade
(ICB). However, the regulatory mechanism of the PD-L1 abundance remains
incompletely understood. Here, we integrated the proteomics of 52
patients with solid tumors and examined immune cell infiltration to
reveal PD-L1-related regulatory modules. Wiskott–Aldrich syndrome
protein (WASP) was identified as a potential regulator of PD-L1 transcription.
In two independent cohorts containing 164 cancer patients, WASP expression
was significantly associated with PD-L1. High WASP expression contributed
to immunosuppressive cell composition, including cells positive for
immune checkpoints (PD1, CTLA4, TIGIT, and TIM3), FoxP3+ Treg cells,
and CD163+ tumor-associated macrophages. Overexpression of WASP increased,
whereas knockdown of WASP decreased the protein level of PD-L1 in
cancer cells without alteration of PD-L1 protein stability. The WASP-mediated
cell migration and invasion were markedly attenuated by the silence
of PD-L1. Collectively, our data suggest that WASP is a potential
regulator of PD-L1 and the WASP/PD-L1 axis is responsible for cell
migration and an immunosuppressive microenvironment.