Aging alters tumor cell - T cell crosstalk to promote breast cancer progression

Abstract Age is a dominant risk factor for all major breast cancer subtypes. However, the mechanisms by which aging influences tumor development remain unclear. Using a novel mouse model whereby breast cancer is induced in situ in young and old wild-type mice via intraductal delivery of a lentivirus encoding the HER2/neu oncogene, we found that old mice exhibited a higher oncogene-induced tumor burden than young mice. Old tumor cells showed reduced expression of interferon-related genes, particularly the T cell-recruiting chemokines Cxcl9 and Cxcl10, linked to their altered chromatin accessibility. CXCL9/10 expression also declined with age in human HER2+ tumors. Correspondingly, old tumors exhibited fewer T cells within tumor lesions. Targeted interventions showed that decreased expression of Cxcl9/10 is responsible for reduced T cell infiltration and weakened anti-tumor immunity. These results show how aged tumor cells are impaired in their recruitment of immune cells, leading to a defective anti-tumor immune response. Competing Interest Statement The authors have declared no competing interest. Data Availability GeoMx, snRNA-seq and snATAC-seq data will be available on Gene Expression Omnibus.