Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity

Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint block-ade need to be resolved. Here, we report that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). We have identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-cata-lyzed production of adenosine, resulting in the suppression of CD8+ T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM21high/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.

Automated summary

We found that elevated CD73 levels due to aberrant turnover were associated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). TRIM21 was identified as the E3 ligase that controls CD73 degradation. Disrupting TRIM21 led to CD73 stabilization, enhanced CD73-catalyzed production of adenosine, and suppression of CD8+ T cell function. Replacement of specific residues on CD73 attenuated CD73 ubiquitylation and degradation, promoting tumor growth and impeding antitumor immunity.