Journal Article

Therapeutic efficacy and mechanism of CD73-TGFβ dual-blockade in a mouse model of triple-negative breast cancer

Ren, Zhi-qiang, Xing, Yun, Jin, Rui, Yu, Ker, Liu, Liang, Pei, Jin-peng

2022

Overview

Although chemotherapy and recently approved immunotherapies have improved treatment of triple-negative breast cancer (TNBC), the clinical outcome for this deadly disease remains unsatisfactory. We found that both cluster of differentiation 73 (CD73) and transforming growth factor (TGF)β were elevated in TNBC and correlated with the epithelial–mesenchymal transition (EMT), fibrotic stroma, an immune-tolerant tumor environment, and poor prognosis. To explore the efficacy of CD73-TGFβ dual-blockade, we generated a bifunctional anti-CD73-TGFβ construct consisting of the CD73 antibody MEDI9447 fused with the TGFβRII extracellular-domain (termed MEDI-TGFβR). MEDI-TGFβR retained full and simultaneous blocking efficiency for CD73 and TGFβ. Compared with MEDI9447 activity alone, MEDI-TGFβR demonstrated superior inhibitory activity against CD73-dependent cell migration and the EMT in CD73-high TNBC cells and effectively reduced lung metastasis in a syngeneic mouse model of TNBC. Mechanistically, the CD73-TGFβ dual-blockade reverted the EMT and stromal fibrosis and induced tumor cell death, which was accompanied by the accumulation of M1-macrophages and production of tumor necrosis factor α (TNFα). The CD73-TGFβ dual-blockade promoted a multifaceted inflammatory tumor microenvironment, as shown by the diminished levels of myeloid-derived suppressor cells (MDSCs) and M2-macrophages, and substantially increased levels of activated dendritic cells, cytotoxic T cells, and B cells. Collectively, our results have highlighted a novel strategy for TNBC treatment.

• Publisher: Springer Nature Singapore,Nature Publishing Group
• Subject: 5'-Nucleotidase - metabolism / Animals / Antigens, Differentiation, B-Lymphocyte / Biomedical and Life Sciences / Biomedicine / Breast cancer / CD73 antigen / Cell death / Cell Line, Tumor / Cell Movement / Chemotherapy / Cytotoxicity / Dendritic cells / Epithelial-Mesenchymal Transition / Fibrosis / Histocompatibility Antigens Class II / Immunology / Immunotherapy / Inflammation / Internal Medicine / Leukocyte migration / Lung cancer / Lymphocytes B / Lymphocytes T / Macrophages / Medical Microbiology / Mesenchyme / Metastases / Mice / Pharmacology/Toxicology / Signal Transduction / Stroma / Suppressor cells / Transforming Growth Factor beta - metabolism / Triple Negative Breast Neoplasms - pathology / Tumor Microenvironment / Tumor necrosis factor-α / Vaccine