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.

Posttranslational protein modifications as gatekeepers of cancer immunogenicity

“…Subsequent immunoprecipitation assays consistently showed CD73 interacting with OTUD4 in TNBC cells, and in situ detection techniques showed the interaction occurred within the cytosol. These findings suggest OTUD4 may drive CD73 accumulation in TNBC ( 3 ). Notably, OTUD4 overexpression heightened levels of membrane-bound CD73 in cancer cells.…”

“…By examining 1,080 TNBC samples from The Cancer Genome Atlas (TGCA) database, the authors showed improvement in patient survival among those with breast tumors exhibiting high CD8 + T cell infiltration and low levels of CD73 expression. The findings determine a notable correlation between the aberrant increase in CD73 expression and the poor prognosis of immune-cold TNBCs ( 3 ).…”

“…In this issue of the JCI , Zhu, Banerjee, and colleagues unveil the potential of the OTU domain-containing protein 4 (OTUD4)/CD73 proteolytic axis as a promising target for bolstering the immunogenicity of TNBC and enhancing the effectiveness of immunotherapy in a complex TME context ( 3 ). The research approach employed multi-omic analyses to investigate the underlying mechanism of the immunosuppressive TME observed in TNBC.…”

“…The research approach employed multi-omic analyses to investigate the underlying mechanism of the immunosuppressive TME observed in TNBC. Through these efforts, the authors identified a distinct immunosuppressive signature within a subset of TNBCs characterized by elevated expression of CD73 ( 3 ).…”

“…CD73 expression in breast cancer cells is regulated via various factors, such as HIF-α and the estrogen receptor (ER), primarily at the transcriptional level. Zhu, Banerjee, and colleagues spotlight the potential impact of CD73’s aberrant posttranslational modifications on the TNBC’s cold TME phenotype ( 3 ). These findings are reminiscent of other immune checkpoint proteins, such as PD-L1, in which posttranslational modifications have a pivotal role in their regulation ( 6 ).…”