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-ß 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.
5'-Nucleotidase , Proteolysis , Triple Negative Breast Neoplasms , Humans , 5'-Nucleotidase/genetics , 5'-Nucleotidase/immunology , 5'-Nucleotidase/antagonists & inhibitors , Female , Mice , Triple Negative Breast Neoplasms/immunology , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Animals , Cell Line, Tumor , GPI-Linked Proteins/immunology , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/antagonists & inhibitors , Neoplasm Proteins/immunology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Ubiquitination
ABSTRACT: A 41-year-old woman with invasive lobular carcinoma of the breast underwent sequential 68Ga-PSMA-11 PET/CT and 18F-fluciclovine PET/CT as part of an ongoing clinical trial (NCT04750473). 68Ga-PSMA PET/CT showed increased radiotracer uptake in the uterine endometrium and left adnexa. 18F-fluciclovine PET/CT showed increased radiotracer uptake in a leiomyomatous uterus. A clinical 18F-FDG PET/CT demonstrated radiotracer uptake in the endometrium and a circumferential area of uptake in the left adnexa, a pattern more similar to the 68Ga-PSMA uptake pattern. This case highlights the discordance in the uptake pattern of 2 radiotracers approved for prostate cancer imaging but increasingly used in non-prostate malignancies imaging.
Fluorodeoxyglucose F18 , Prostatic Neoplasms , Male , Humans , Adult , Positron Emission Tomography Computed Tomography/methods , Gallium Radioisotopes , Prostatic Neoplasms/pathology , Uterus/pathology
