Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis
Rebeca Uceda-Castro, Andreia S. Margarido, Lesley Cornet, Serena Vegna, Kerstin Hahn, Ji‐Ying Song, Diana A. Putavet, Mariska van Geldorp, Ceren H. Çitirikkaya, Peter L.J. de Keizer, Leon C. ter Beek, Gerben R. Borst, Leila Akkari, Olaf van Tellingen, Marike L. D. Broekman, Claire Vennin, Jacco van Rheenen
Abstract
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.