Macrophages suppress CD8 + T cell cytotoxic function in triple negative breast cancer via VISTA
Menée à l'aide d'une lignée cellulaire et d'un modèle murin de cancer du sein triple négatif, cette étude met en évidence un mécanisme par lequel les macrophages suppriment la fonction cytotoxique des lymphocytes T CD8+ via l'expression de la protéine transmembranaire VISTA
Background : 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.
Method : 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.
Results : 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.
Conclusion : These findings provide the rationale for the development of anti-VISTA targeting strategies in the treatment of TNBC.
British Journal of Cancer , article en libre accès 2025