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Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers
Yueming Zhu, … , Bin Zhang, Yong Wan
Yueming Zhu, … , Bin Zhang, Yong Wan
Published March 26, 2024
Citation Information: J Clin Invest. 2024;134(10):e176390. https://doi.org/10.1172/JCI176390.
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Research Article Oncology Article has an altmetric score of 17

Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers

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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.

Authors

Yueming Zhu, Anupam Banerjee, Ping Xie, Andrey A. Ivanov, Amad Uddin, Qiao Jiao, Junlong Jack Chi, Lidan Zeng, Ji Young Lee, Yifan Xue, Xinghua Lu, Massimo Cristofanilli, William J. Gradishar, Curtis J. Henry, Theresa W. Gillespie, Manali Ajay Bhave, Kevin Kalinsky, Haian Fu, Ivet Bahar, Bin Zhang, Yong Wan

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Figure 1

Accumulation of CD73 is dramatically associated with an unfavorable tumor immune response and prognosis in immune-suppressive breast cancers.

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Accumulation of CD73 is dramatically associated with an unfavorable tumo...
(A) Proteomic analysis of 59 immune-related proteins in TCGA samples of PAM50-defined intrinsic and hormone receptor subtypes, including 19 TNBC, 13 luminal A, 17 luminal B, and 10 Her2+ breast tumors. (B) Heatmap and hierarchical clustering are based on the expression levels of the 309 immune-related proteins — differentially expressed in 4 breast cancer types. Each column represents a sample; each row represents a protein. The log2 relative protein expression scale is depicted on the top left. (C) Volcano plots showing the immune-related protein expression changes in 2 TNBC patient cohorts. Each circle represents 1 protein. The log fold change is represented on the x-axis. The y-axis shows the FDR adjusted log10 of the P value. (D) CD73 and PD-L1 expression density in 2 TNBC groups were calculated based on log2 relative protein expression. (E) mRNA analysis of immune-relevant proteins in 37 specimens from patients with TNBC from the GEO database. The genes (rows) are sorted according to the difference between the average mRNA levels in breast cancer types. (F) Breast cancer specimens TMA stained with an anti-CD73 antibody and representative pictures of different breast cancer subtypes are shown. Scale bars: 100 μm.(G) Quantified TMA consisting of luminal A, luminal B, Her2+, and TNBC samples immune stained for CD73. (H) The expression of CD73 in normal human mammary epithelial cells and various subtypes of breast cancer cells was detected by immunoblotting using an anti-CD73 antibody. (I) Kaplan-Meier curves using multivariable Cox proportional hazard model for the corresponding CD8+ T cells and CD73 expression. A total n = 1,100 breast cancer patients were included in the study, with 20 cases having missing data. The analysis was performed on the remaining 1,080 patients, of whom 153 had died, and Kaplan-Meier curves were subsequently plotted. Low- and high-expression groups refer to patients with expression levels lower and greater than the 50th percentile, respectively. **P < 0.01, ***P < 0.001, and ****P < 0.0001, statistical significance was determined by 1-way ANOVA with Tukey’s multiple comparisons test for immunostaining using n = 110 breast samples.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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