Understanding Treg-mediated modulation of microglia in breast cancer brain metastasis - PROJECT SUMMARY Metastatic brain tumors represent the most common form of malignancy in the central nervous system. In women with metastatic breast cancer, up to 35% of patients will suffer from brain metastasis and will have little to no therapeutic options to treat them. Current treatments are often complicated by the protected environment of the brain with its blood-brain barrier, distinct anatomical structure, metabolism, and unique immune composition. Given the high prevalence of breast cancer in women in the United States, this poses a significant unmet clinical need. Immune modulation represents a promising therapeutic approach, but the efficacy of these treatments is often hindered by the presence of suppressive immune cells, such as regulatory T cells (Tregs). Tregs are a population of immunosuppressive cells that serve to control immune responses and prevent autoimmunity. Tregs have been reported to be present in brain metastases and have been used as a prognostic factor in tumor progression and patient outcomes. Systemic depletion of Tregs can promote anti-tumor immunity, but this approach also confers unwanted systemic autoimmunity. Thus, specific mechanisms to target Treg function in the brain without completely depleting them is necessary. My preliminary data demonstrates that Tregs accumulate readily within brain metastases and their depletion confers a complete elimination of tumor mass. This response results from an enhanced effector T cell infiltration and an enriched antigen presentation program in microglia, the brain-resident macrophage population. Co-depletion of microglia in Treg depleted mice results in a complete reversal of this tumor rejection. This emphasizes the central role that microglia play in the anti-tumor response in brain metastases and demonstrates a need to target Treg-microglia interactions in this setting. To this end, the proposed study will aim to understand and target Treg modulation of microglia, allowing for the potent and brain-specific targeting of Treg function. First, I will determine if antigen presentation is a central microglial function suppressed by Tregs to identify targets to inhibit Treg function specifically within the brain. I will also assess the therapeutic potential of deleting CD73, an ecto-5’-nucleotidase expressed on Tregs that converts AMP into adenosine, which has been shown to suppress microglia function through A3R, an adenosine receptor exclusive to microglia. This work will pave the path to the generation of novel therapeutics to impair Treg-mediated suppression in the brain and generate desperately needed treatments for patients with brain metastases.
