Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis

An increasing number of breast cancer patients develop brain metastases (BM). Standard-of-care treatments are largely inefficient, and breast cancer brain metastasis (BCBM) patients are considered untreatable. Immunotherapies are not successfully employed in BCBM, in part because breast cancer is a “cold” tumor and also because the brain tissue has a unique immune landscape. Here, we generate and characterize immunocompetent models of BCBM derived from PyMT and Neu mammary tumors to test how harnessing the pro-senescence properties of doxorubicin can be used to prime the specific immune BCBM microenvironment. We reveal that BCBM senescent cells, induced by doxorubicin, trigger the recruitment of PD1-expressing T cells to the brain. Importantly, we demonstrate that induction of senescence with doxorubicin improves the efficacy of immunotherapy with anti-PD1 in BCBM in a CD8 T cell-dependent manner, thereby providing an optimized strategy to introduce immune-based treatments in this lethal disease. In addition, our BCBM models can be used for pre-clinical testing of other therapeutic strategies in the future. [Display omitted] •Generation of two mouse breast cancer brain metastasis (BCBM) models•Doxorubicin induces a senescence program in BCBM•Senescent cells in BCBM recruits PD1+ T cells to BCBM•Doxorubicin pre-treatment improves immune checkpoint blockade in BCBM Uceda-Castro et al. generate two models of BCBM to optimize immunotherapy in this disease, which is considered untreatable. They demonstrate that doxorubicin induces senescence and in turn triggers a recruitment of PD1+ T cells. Combining doxorubicin with anti-PD1 significantly improves survival, in a CD8+ T cell-dependent manner.