Immune microenvironment in brain metastais

About This Grant

Project Summary/Abstract Brain metastasis is a lethal disease and major clinical unmet need for breast cancer patients. There is growing interest in immunotherapies to treat central nervous system (CNS) cancers, but greater understanding of the unique immune microenvironment of the brain is needed to develop effective treatment strategies. The brain contains a unique type of tissue resident macrophage called microglia that constitute 10-15% of brain cells and play diverse functions in CNS homeostasis and disease. In recent work, we found that microglia are central regulators of the anti-tumor T cell response and are critical to suppress brain metastasis (Evans et al., Nature Cell Biology, 2023). In this renewal proposal application, we will investigate three key gaps in knowledge raised during this work: 1) how do microglia promote the T cell response? Although microglia are principally known as phagocytes, but we observe a robust upregulation of antigen presentation machinery in response to brain metastasis. In Aim 1, we will test the hypothesis that microglia promote the T cell response primarily through local antigen presentation in the CNS and that they are main source of this function. 2) Why does disease continue to progress in many animals despite a robust immune response? In Aim 2, we will test the hypothesis that our observed accumulation of Tregs is a main mechanism for disease progression through direct suppression of microglia in the CNS. 3) How do microglia initially become activated in response to brain metastasis? We observe that they rapidly sense and home to sites of infiltrating cancer cells. In Aim 3, we will test the hypothesis that the purinergic receptor P2RY12 that mediates chemotaxis in other brain disease settings is essential for microglia activation and chemotaxis to metastasis. Each of these phases of the microglia response – their initial activation, their regulation of adaptive immunity, and their potential suppression in advanced metastasis - present new potential opportunities for therapeutic targeting in brain metastasis.