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 after 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 state that is associated with immune dysfunction, and we find that the tumor-derived, stem cell/basal cell protein 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 immunosuppression 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.

Automated summary

This study reveals that dormant tumor cells can evade immune detection by utilizing tolerance mechanisms to alter the T cell microenvironment. The researchers found that dormant tumor cells can initiate immune responses but also promote the accumulation of regulatory T cells, inhibiting the activity of CD8+ killer T cells. Additionally, a protein called DKK3 derived from the tumor cells is critical for this suppression of the immune system and is associated with poor survival and immunosuppression in human breast cancers. Targeting these mechanisms, such as DKK3, may render dormant tumors susceptible to immunotherapies.