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-β1. 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-γ and TNF-α. 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.

中文翻译：

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T细胞中前蛋白转化酶弗林蛋白酶的缺失抑制了癌基因驱动的三阴性乳腺癌中的乳腺肿瘤发生。

免疫治疗干预已成为包括三阴性乳腺癌（TNBC）在内的各种癌症类型的重要治疗方法。先前的研究表明，由于proTGF-β1的裂解受损，T细胞特异性弗林蛋白酶缺陷小鼠表现出调节性CD4 + T细胞（Tregs）故障表型。然而，尚不清楚该表型如何影响TNBC中的肿瘤起始和进展。在这里，我们首先表明，与其他前蛋白转化酶成员相比，不同免疫细胞中弗林蛋白酶的表达水平更高，一旦免疫细胞被激活，其表达明显上调。此外，弗林蛋白酶的表达水平与TNBC肿瘤样品中大量不同的浸润免疫细胞负相关。在致癌基因诱导的TNBC小鼠模型中，我们证明，T细胞中弗林蛋白酶失活会抑制原发性肿瘤的生长和肺转移。这些小鼠的T细胞中弗林蛋白酶的破坏导致外周和肿瘤浸润Treg降低。结果，浸润肿瘤的CD8 + T细胞显示出强大的增殖能力，并上调了IFN-γ和TNF-α的表达。在这些小鼠中，抑制的肿瘤生长与诱导的细胞凋亡有关，这导致减少的肺转移瘤形成。综上所述，这些发现揭示了靶向弗林蛋白酶在癌症中的潜在治疗益处，特别是对于治疗TNBC的免疫治疗干预。肿瘤浸润的CD8 + T细胞显示出强大的增殖能力，并上调IFN-γ和TNF-α的表达。在这些小鼠中，抑制的肿瘤生长与诱导的细胞凋亡有关，这导致减少的肺转移瘤形成。综上所述，这些发现揭示了靶向弗林蛋白酶在癌症中的潜在治疗益处，特别是对于治疗TNBC的免疫治疗干预。肿瘤浸润的CD8 + T细胞显示出强大的增殖能力，并上调IFN-γ和TNF-α的表达。在这些小鼠中，抑制的肿瘤生长与诱导的细胞凋亡有关，这导致减少的肺转移瘤形成。综上所述，这些发现揭示了靶向弗林蛋白酶在癌症中的潜在治疗益处，特别是对于治疗TNBC的免疫治疗干预。