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

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)beta 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-TGF beta dual-blockade, we generated a bifunctional anti-CD73-TGFP construct consisting of the CD73 antibody MEDI9447 fused with the TGWU extracellular-domain (termed MEDI-TGFOR). MEDI-TGFOR retained full and simultaneous blocking efficiency for CD73 and TGF beta. Compared with MEDI9447 activity alone, MEDI-TGFOR 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-TGF beta 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 alpha (TNF alpha). The CD73-TGF beta 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.

Automated summary

CD73 and TGF beta expression are associated with poor prognosis and tumor microenvironment changes in TNBC. Dual blockade of CD73 and TGF beta can inhibit cell migration, reverse EMT and fibrosis, induce tumor cell death, and modify the tumor microenvironment to have multifaceted inflammatory features.