Breast cancer cells survive chemotherapy by activating robust, parallel programs of immune checkpoint expression

Breast cancer cells that survive chemotherapy to cause relapse must avoid intrinsic and extrinsic mechanisms of cell death. Entry into senescence enables survival from mitotic catastrophe, apoptosis, and nutrient deprivation, but mechanisms used to evade immune mediated removal are unclear. We show here that human and mouse breast tumor cells that survive chemotherapy activate complex programs of immune modulation including clinically relevant checkpoints. scRNA-seq and cell imaging revealed distinct populations of cells in residual disease that have activated pathways related to either interferon signaling, typified by PD-L1 expression, or p53 signaling, typified by CD80 expression. In vivo, treatment of mammary tumors with chemotherapy followed by targeting of the PD-L1 and/or CD80 axes improved response, including complete eradication in some instances. Unfortunately, however, even combination strategies failed to fully eradicate the tumor in the majority of cases. Our findings reveal the formidable challenge of eliminating residual disease populated by senescent cells that express multiple redundant immune inhibitory pathways and suggest rational strategies are needed based on the specific checkpoint pathways expressed in residual disease. scRNA-seq of CD45-positive immune cells and CD4/8-positive T-cells, ATAC-seq of mammary tumor cells, and RNA-seq of mammary tumor cells