Graduate Student Univ. of California, Irvine, United States
Introduction/Rationale: Breast cancer brain metastasis (BCBM) is linked with dismal outcomes. Current therapies fail due to their inability to cross the blood-brain barrier (BBB). Targeting immune cells in BCBM has garnered interest since immune cells naturally cross the BBB. Thus, there is a critical need to elucidate the immune microenvironment within BCBM. Regulatory T cells (Tregs) are immunosuppressive T cells implicated in several malignancies. However, their functions remain poorly understood in BCBM.
Methods: Here we utilize Foxp3-DTR mice to ablate Tregs in a murine model of BCBM and assess changes in tumor burden and immune activation by flow cytometry. Tregs were depleted systemically or locally to distinguish peripheral and brain-specific effects. We also examined the importance of Treg interactions with microglia, the brain-resident macrophage, through co-depletion using the CSF1R inhibitor PLX5622.
Results: Our data shows that Tregs readily infiltrate the brain in BCBM. Systemic Treg depletion in BCBM-bearing mice led to a massive accumulation of T cells and complete clearance of metastasis. We also found that microglia displayed a robust antigen presentation phenotype in Treg-depleted mice. Localized Treg depletion resulted in preferential expansion of conventional CD4 T cells (Tconv) 24h after Treg depletion and enrichment of antigen presentation in microglia at 48h. In situ analysis showed that Tregs and microglia co-localize at the tumor-stroma interface, indicating crosstalk between them. Strikingly, microglia depletion reversed tumor clearance after Treg loss and significantly reduced Tconv infiltration.
Conclusion: Our data demonstrates that Tregs are central to BCBM progression through suppression of microglial antigen presentation and effector T cell responses. These findings identify Treg-mediated suppression of microglia as a central axis of immunosuppression in BCBM and a promising immunotherapeutic target.
