Abstract
Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade 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-catalyzed 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.
| Original language | English (US) |
|---|---|
| Article number | eadd6626 |
| Journal | Science Advances |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2023 |
Funding
Acknowledgments: W e thank the proteomic core at the Feinberg School of Medicine at Northwestern University for mass spectrometry analysis and postdata analysis (NCI CCSG P30 CA060553 and P41 GM108569). W e thank all members of the W an and Zhang labora tories for helpful discussion. This work was also supported by the RHLCCC Flow Cytometry Fa cility , Immunotherapy Assessment Core, Image CORE, Animal Resources Fa cility , and a Cancer Center Support Grant (NCI CA060553). Funding: This work was supported by NIH R01CA258857, NIH R01CA258765, NIH R01CA250110, and NIH R01CA202948. This work was also partially supported by Northwestern University Friends of Prentice A ward SP0052611. Author contributions: Y .W ., B.Z., Z.F ., S.C., and Y .Z. conceived the project. Y .W . and B.Z. supervised research. Z.F ., S.C., Y .Z., D.Z., P .X., Q.J., J.C., S.X., and Y .X. performed research. Y .W ., B.Z., Z.F ., S.C., and Y .Z. analyzed and interpreted data. D.Z., Y .X., X.L., and X.S. performed bioinformatic and computational analyses. Z.F ., Y .Z., S.C., D.Z., and P .X. produced figures with input from Y .W ., B.Z., and X.L. M.C., W .J.G., K.K., and Y .Y . oversaw clinical bioinformatic analyses. Y .Z., Z.F ., S.C., Z.B., and Y .W . wrote the manuscript with input from all authors. All authors discussed the results and commented on the manuscript. Competing interests: The authors declare that they hav e no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
ASJC Scopus subject areas
- General
