Inhibiting CDA for checkpoint inhibitor-resistant cancers

Inhibiting CDA — a pyrimidine salvage pathway enzyme that is overexpressed in cancer cells, and increases extracellular uridine diphosphate levels to recruit immunosuppressive tumor associated macrophages (TAMs) — could help treat immunotherapy-resistant tumors.

Bioinformatic analyses of pan-cancer RNA-sequencing from patient tumors responsive and resistant to immune checkpoint blockade identified CDA as a top metabolic gene in resistant tumors. CDA mRNA and protein expression levels were increased in pancreatic, colon, gastric, and esophageal cancer patient tumors compared with corresponding normal adjacent tissue, and were correlated with expression of immunosuppressive tumor microenvironment hallmarks. ...