TY - JOUR
T1 - Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers
AU - Zhu, Yueming
AU - Banerjee, Anupam
AU - Xie, Ping
AU - Ivanov, Andrey A.
AU - Uddin, Amad
AU - Jiao, Qiao
AU - Chi, Junlong Jack
AU - Zeng, Lidan
AU - Lee, Ji Young
AU - Xue, Yifan
AU - Lu, Xinghua
AU - Cristofanilli, Massimo
AU - Gradishar, William J.
AU - Henry, Curtis J.
AU - Gillespie, Theresa W.
AU - Bhave, Manali Ajay
AU - Kalinsky, Kevin
AU - Fu, Haian
AU - Bahar, Ivet
AU - Zhang, Bin
AU - Wan, Yong
N1 - Publisher Copyright:
Copyright: © 2024, Zhu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2024/5/15
Y1 - 2024/5/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85190066213
U2 - 10.1172/JCI176390
DO - 10.1172/JCI176390
M3 - Article
C2 - 38530357
AN - SCOPUS:85190066213
SN - 0021-9738
VL - 134
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
M1 - e176390
ER -