Team: Elga de Vries, Yvette van Kooyk
The central nervous system (CNS) immune responses can have opposite effects on disease outcome. The altered brain microenvironment and consequent attraction of (auto)reactive immune cells into the CNS are key detrimental events in a large number of neurological disorders and contribute to disease pathology. In contrast, in brain tumours such as glioblastoma, or metastatic solid tumours that infiltrate into the brain, the tumour micro-environment actively limits the infiltration of tumour reactive immune cells, while stimulating accumulation of immune suppressive immune cells, together resulting into uncontrolled tumour growth and its recurrence. These opposite effects on the immune system drive on local alterations in the CNS microenvironment (activation/suppression) that change during disease onset and progression, such as sialylation and lipid signatures. Ways to unravel these mechanisms to either inhibit the infiltration of (auto)reactive immune cells in neurological disorders, whilst promoting their entry and reduce accumulation of suppressive immune cells into brain tumours or metastatic solid tumours, may provide innovative ways to fight such detrimental disorders. However, to date we lack fundamental understanding of underlying pathways that control immune cell infiltration (T cells and myeloid cells) in these opposite suppressive/ permissive situations in the brain. We here hypothesize that immune cell infiltration is controlled by environmental CNS alterations. Unravelling such pathways will uncover whether there are common denominators that can be modulated to fight disease and in future enhance therapies (drug delivery, CAR-T cell approach).
Therefore, the overall aim of the Adore Crossing immune barriers proposal is to define how the brain microenvironment controls immune cell infiltration into the CNS during health (healthy age continuum, incl 100-plus cohort) and in the neurological disorders multiple sclerosis (MS) and Alzheimer’s disease (AD) and the oncological disorder glioblastoma (GBM) and brain metastatic lung tumours and melanoma. In the current project, we will conduct fundamental research into (1) to what extent immune cells (T cells and myeloid cells) are present in the healthy brain and what is its microenvironment related to immune metabolic mediators such as sialylation and glycolipids, (2) which mechanisms underlie immune cell migration across the brain barrier in context of disease, and (3) decipher the role of the brain microenvironment in these conditions to ultimately come to novel targets for treatment to combat brain disorders.
Our specific aims are to:
- Define the role of modulated pathways on immune cell trafficking across the brain barriers in the context of MS, AD, GBM and brain metastatic lung cancer and melanoma using human measurement models.
- Define the brain microenvironment contributing to (lack of) immune cell infiltration in health vs. disease, specifically in MS, AD, (the periphery of) GBM tumours, and brain metastatic lung cancer and melanoma. Specific focus is on immune cell profiling, vascular alterations, and myeloid status and how this relates to glycan and lipid profiles.
- Uncover the role of identified alterations in the (tumour/brain) microenvironment in myeloid cellular function. Essential pathways will be modulated in appropriate models using either CRISPR/CAS9 or lentiviral technology or pharmacological manipulation.
