Senescent fibroblasts support tumor growth by inducing immune cell death in humanized models

Syngeneic mouse models revealed that senescence influences the tumor immune response in many ways by, for example, inducing an immunosuppressive microenvironment or by favoring immune cell recruitment. Yet, the impact of senescence on the tumor immune response in a humanized setting is mostly unknown. Here, using tumor spheroids and humanized mice bearing tumors immunogenic to autologous human immune cells, we show that senescent fibroblasts exert a dual impact on the tumor immune response by attracting more immune cells but also by inducing the death of T and NK cells. Mechanistically, we demonstrate that this was mostly the result of increased Fas ligand (FasL) expression at the surface of senescent fibroblasts and that the deletion of FasL was sufficient to prevent immune cell death and increase tumor cell killing. Our results highlight the importance of evaluating the impact of therapy-induced senescence in humanized models to better understand and predict the outcome of cancer treatments.