Refine
Has Fulltext
- yes (2)
Is part of the Bibliography
- yes (2) (remove)
Year of publication
- 2023 (2) (remove)
Document Type
- Journal article (2)
Language
- English (2) (remove)
Keywords
- Parkinson's disease (1)
- T cells (1)
- antigen-presenting cells (1)
- cancer microenvironment (1)
- immunotherapy (1)
- neuroimmunology (1)
- tumour immunology (1)
Institute
- Medizinische Klinik und Poliklinik II (2)
- Frauenklinik und Poliklinik (1)
- Institut für Molekulare Infektionsbiologie (1)
- Institut für Virologie und Immunbiologie (1)
- Kinderklinik und Poliklinik (1)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (1)
- Neurologische Klinik und Poliklinik (1)
- Theodor-Boveri-Institut für Biowissenschaften (1)
EU-Project number / Contract (GA) number
- 825575 (1)
Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut.
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.