Advertisement
ResearchIn-Press PreviewOncologyTherapeutics Open Access | 10.1172/JCI176390
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Zhu, Y. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Banerjee, A. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Xie, P. in: JCI | PubMed | Google Scholar |
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Ivanov, A. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Uddin, A. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Jiao, Q. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Chi, J. in: JCI | PubMed | Google Scholar |
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Zeng, L. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Lee, J. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Xue, Y. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Lu, X. in: JCI | PubMed | Google Scholar |
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Cristofanilli, M. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Gradishar, W. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Henry, C. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Gillespie, T. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Bhave, M. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Kalinsky, K. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Fu, H. in: JCI | PubMed | Google Scholar |
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Bahar, I. in: JCI | PubMed | Google Scholar
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Zhang, B. in: JCI | PubMed | Google Scholar |
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, United States of America
2Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States of America
3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States of America
5Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
6Department of Medicine, Weill Cornell Medicine, New York, United States of America
7Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwest University Feinberg School of Medicine, Chicago, United States of America
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America
Find articles by Wan, Y. in: JCI | PubMed | Google Scholar
Published March 26, 2024 - More info
Despite widespread utilization of immunotherapy, challenge to treat immune-cold tumors needs to be resolved. 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 that inhibits 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 a novel strategy for targeting immunosuppressive OTUD4-CD73 proteolytic axis in treating immune-suppressive breast cancers with the inhibitor ST80.