Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma

CD73, a cell‐surface N‐linked glycoprotein that produces extracellular adenosine, is a novel target for cancer immunotherapy. Although anti‐CD73 antibodies have entered clinical development, CD73 has both protumor and antitumor functions, depending on the target cell and tumor type. The aim of this study was to characterize CD73 regulation in human hepatocellular carcinoma (HCC). We examined CD73 expression, localization, and activity using molecular, biochemical, and cellular analyses on primary HCC surgical specimens, coupled with mechanistic studies in HCC cells. We analyzed CD73 glycan signatures and global alterations in transcripts encoding other N‐linked glycoproteins by using mass spectrometry glycomics and RNA sequencing (RNAseq), respectively. CD73 was expressed on tumor hepatocytes where it exhibited abnormal N‐linked glycosylation, independent of HCC etiology, tumor stage, or fibrosis presence. Aberrant glycosylation of tumor‐associated CD73 resulted in a 3‐fold decrease in 5′‐nucleotidase activity (P