Dormant tumors circumvent tumor-specific adaptive immunity by establishing a Treg-dominated niche via DKK3

Approximately 30% of breast cancer survivors deemed 'free of disease' will experience locoregional or metastatic recurrence even up to 30 years post initial diagnosis, yet how residual/dormant tumor cells escape immunity elicited by the primary tumor remains unclear. We demonstrate that intrinsically dormant tumor cells are indeed recognized and lysed by antigen-specific T cells in vitro and elicit robust immune responses in vivo. However, despite close proximity to CD8+ killer T cells, dormant tumor cells themselves support early accumulation of protective FoxP3+ T regulatory cells (Tregs), which can be targeted to reduce tumor burden. These intrinsically dormant tumor cells maintain a hybrid epithelial/mesenchymal or stem-like state, which is associated with immune dysfunction, and we find the tumor-derived stem/basal gene Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) is critical for Treg inhibition of CD8+ T cells. We also demonstrate that DKK3 promotes immune-mediated progression of proliferative tumors and is significantly associated with poor survival and immune suppression in human breast cancers. Together, these findings reveal that latent tumors can use fundamental mechanisms of tolerance to alter the T cell microenvironment and subvert immune detection. Thus, targeting these pathways, such as DKK3, may help render dormant tumors susceptible to immunotherapies. Overall design: D2A1 or D2.1 mouse mammary tumor cells were implated into the mammary fat pad of female Balb/c or SCID-beige mice (10^6/mouse). Tumors were collected upon reaching ~500 for bulk RNAseq. Cultured cells were also collected in triplicate for RNAseq.