Loss of the proprotein convertase Furin in T cells represses mammary tumorigenesis in oncogene-driven triple negative breast cancer

摘要

Immunotherapeutic interventions have become an important treatment for various cancer types including triple negative breast cancer (TNBC). Previous studies have shown that T cell-specific Furin deficient mice show regulatory CD4(+) T cells (Tregs) malfunction phenotypes due to impaired cleavage of proTGF-beta 1. However, it is unknown how this phenotype influences tumor initiation and progression in TNBC. Here, we first show that there is a higher level of Furin expression in different immune cells compared to other proprotein convertase members, and its expression is clearly upregulated once immune cells are activated. Moreover, Furin expression levels negatively correlated with an abundance of different infiltrating immune cells in TNBC tumor samples. In an oncogene-induced TNBC mouse model, we demonstrate that Furin inactivation in T cells inhibits primary tumor growth and lung metastasis. Disruption of Furin in T cells in these mice led to a decreased peripheral and tumor-infiltrating Tregs. As a consequence, tumor-infiltrating CD8(+) T cells showed a strong proliferative capacity and upregulated expression of IFN-gamma and TNF-alpha. In these mice the repressed tumor growth was associated with induced apoptosis, which led to reduced lung metastases formation. Taken together, these finding revealed the potential therapeutic benefit of targeting Furin in cancer, particularly for immunotherapeutic interventions to treat TNBC.