Abudula Maidinaimu, Astuti Yuliana, Raymant Meirion, Sharma Vijay, Schmid Michael C, Mielgo Ainhoa
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
School of Medicine and Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
Br J Cancer. 2025 May 2. doi: 10.1038/s41416-025-03013-5.
Immunotherapy targeting negative immune checkpoint regulators to enhance the anti-tumour immune response holds promise in the treatment of TNBC. V-domain Ig suppressor of T-cell activation (VISTA) is an immune checkpoint molecule, known to be upregulated and involved in modulating tumour immunity in TNBC. However, how VISTA affects immune response and its therapeutic potential in TNBC remains unclear.
Here, we examined VISTA expression and cellular distribution in TNBC patients' samples and pre-clinical TNBC mouse model. Functional assays were performed to assess the impact of VISTA blockade on macrophage phenotypes, CD8 + T cell infiltration and activation, and overall anti-tumour immune response.
In this study we show that VISTA expression levels are increased in TNBC patients' samples and pre-clinical mouse models compared to non-involved breast tissue and VISTA is mainly expressed on tumour infiltrating macrophages and neutrophils. Blocking VISTA reverts macrophages immunosuppressive phenotypes, increases CD8 + T cell infiltration and activation, and enhances an anti-tumour immune response. Mechanistically, we show that neutralising VISTA on macrophages enhances their immune-stimulatory functions and inhibits the suppressive effect of macrophages on CD8 + T cells activation.
These findings provide the rationale for the development of anti-VISTA targeting strategies in the treatment of TNBC.
靶向负性免疫检查点调节因子以增强抗肿瘤免疫反应的免疫疗法在三阴性乳腺癌（TNBC）治疗中具有前景。T细胞活化V结构域免疫球蛋白抑制因子（VISTA）是一种免疫检查点分子，已知在TNBC中上调并参与调节肿瘤免疫。然而，VISTA如何影响免疫反应及其在TNBC中的治疗潜力仍不清楚。
在此，我们检测了TNBC患者样本和临床前TNBC小鼠模型中VISTA的表达及细胞分布。进行功能试验以评估VISTA阻断对巨噬细胞表型、CD8 + T细胞浸润和活化以及整体抗肿瘤免疫反应的影响。
在本研究中，我们发现与未受累乳腺组织相比，TNBC患者样本和临床前小鼠模型中VISTA表达水平升高，且VISTA主要表达于肿瘤浸润巨噬细胞和中性粒细胞上。阻断VISTA可逆转巨噬细胞的免疫抑制表型，增加CD8 + T细胞浸润和活化，并增强抗肿瘤免疫反应。从机制上来说，我们表明中和巨噬细胞上的VISTA可增强其免疫刺激功能，并抑制巨噬细胞对CD8 + T细胞活化的抑制作用。
这些发现为开发抗VISTA靶向策略用于TNBC治疗提供了理论依据。
