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

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 7

Spatially resolved signatures pertaining to OTUD4hi/CD73hi are associated with unfavorable immune responses.

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Spatially resolved signatures pertaining to OTUD4hi/CD73hi are associate...
(A) Representative staining of OTUD4, CD73 and PanCK, followed by the selection of regions of interest (ROI) and subsequent autosegmentation in TNBC tissue sections (n = 30) using DSP. Scale bars: 100 μm. (B) The analysis of OTUD4 and CD73 protein expression on TNBC (n = 30) using ImageJ showing the positive correlation between OTUD4 with CD73. Scale bars: 50 μm. (C–E) DAVID functional gene onology (GO) analysis of molecular function (MF) on the DEGs (different expressional genes) in tumor epithelial compartment (PanCK+) between OTUD4-high expression cases and OTUD4-low expression cases (C), revealing decreased Ubl conjugation (D) and increased TGF-β signaling activity (E) in OTUD4-high expression tumors; (F–H) DAVID REACTOME analysis of DEGs in nontumor areas between OTUD4-high expression cases and OTUD4-low expression cases (F), highlighting increased TCR signaling, NFκB activation (G) and induction of IFN-α/β (H) in patients with OTUD4-low expression; (I–K) Gene set enrichment analysis (GSEA) demonstrating positive enrichment of hallmark curated gene sets for IFN-α response (I), IFN-γ response (J), and IL-2-STAT5 signaling (K) in nontumor areas of OTUD4-low expression cases compared with OTUD4-high expression cases. Data (mean ± SEM) are representative of at least 3 independent experiments. *P < 0.05, by 1-way ANOVA with Tukey’s multiple comparisons test.