Abstract
Despite widespread utilization of immunotherapy, treating immune-cold tumors remains a challenge. Multiomic analyses and experimental validation identified the OTUD4/CD73 proteolytic axis as a promising target in treating immune-suppressive triple negative breast cancer (TNBC). Mechanistically, deubiquitylation of CD73 by OTUD4 counteracted its ubiquitylation by TRIM21, resulting in CD73 stabilization inhibiting tumor immune responses. We further demonstrated the importance of TGF-β signaling for orchestrating the OTUD4/CD73 proteolytic axis within tumor cells. Spatial transcriptomics profiling discovered spatially resolved features of interacting malignant and immune cells pertaining to expression levels of OTUD4 and CD73. In addition, ST80, a newly developed inhibitor, specifically disrupted proteolytic interaction between CD73 and OTUD4, leading to reinvigoration of cytotoxic CD8+ T cell activities. In preclinical models of TNBC, ST80 treatment sensitized refractory tumors to anti-PD-L1 therapy. Collectively, our findings uncover what we believe to be a novel strategy for targeting the immunosuppressive OTUD4/CD73 proteolytic axis in treating immune-suppressive breast cancers with the inhibitor ST80.
| Original language | English (US) |
|---|---|
| Article number | e176390 |
| Journal | Journal of Clinical Investigation |
| Volume | 134 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2024 |
Funding
We are grateful to Wade Harper and Jianping Jin (both from Harvard University, Boston, Massachusetts, USA) for kindly providing the TAP purification vector. Ziyi Fu and Shipeng Xu (both from Northwestern University, Chicago, Illinois, USA) participated in part of the plasmid construction and protein purification. Satyaki Saha (Stony Brook University, Stony Brook, New York, USA) carried out the coevolution analysis of the interacting proteins. We appreciate Winship Cancer Institute Flow Cytometry Facility, Image CORE, and Animal Resources Facility at Emory University School of Medicine (Winship Cancer Institute-NIH 5P30CA138292). We appreciate the proteomic core at the Feinberg School of Medicine Northwestern University for Mass Spectrometry Analysis and post data analysis (NCI CCSG P30 CA060553 and P41 GM108569). This work was also supported by the Northwestern University Immunotherapy Assessment Core, Pathology Core Facility, RHLCCC Flow Cytometry Facility, and Animal Resources Facility (NCI CA060553). We thank all members of the Wan, Zhang, and Bahar laboratories for their helpful discussion. This work was supported by the Emory SOM Endowed fund and part of the effort of YW is covered by NIH R01CA258857, NIH R01CA258765, NIH R01CA250110, NIH R01CA202948, and Winship Invest$ fund. Support from the NIH grants P01 DK096990 and R01 GM139297 is gratefully acknowledged by IB. This work was partially supported by NIH R01CA222963, R01CA250101, and R01CA258857 for BZ. This work was also partially supported by the NCI\u2019s Informatics Technology for Cancer Research Program (R21CA274620, AAI) and NCI Emory Lung Cancer SPORE Career Enhancement Program (AAI, P50CA217691).
ASJC Scopus subject areas
- General Medicine
