Invigorating immunity against brain metastases in lung and breast cancer patients
Brain metastases (BrMet) are a devastating complication in breast and lung cancer and a main cause of death. Novel immunotherapies have revolutionized treatment of cancer, but response rates are hard to predict, especially for BrMet patients. We have quantified immune cells in BrMet tissue of patients with lung or breast cancer and observed a higher number of T cells compared to primary brain tumours, but also a high heterogeneity in T-cell numbers. Interestingly, high infiltration of T cells in BrMet was associated with longer survival of patients. We hypothesize that immune cell infiltration and function in BrMet is regulated by the tumour microenvironment (TME), and an improved understanding of niche-specific factors, cell types, and mechanisms will help to improve immunotherapy in BrMet patients. In ImmuMet, we will characterize the BrMet niche in patient-derived tissues and blood, PDX and immunocompetent mouse models to define TME subclasses and unravel clinical associations. We will acquire single-cell and spatial tissue data, multiplexed flow cytometry, and serum analyses, combined with integrative bioinformatics and modelling approaches, including own and publicly available data, to build a knowledge base that guides the selection of candidate genes, pathways, cellular interactions, and molecular mechanisms, which we will validate and modulate in established patient-derived organoid and mouse models. The ImmuMet consortium benefits from the complementary expertise of wet lab scientists with a strong research focus on tumour immunology and BrMet biology, clinicians who are at the forefront of treatment decisions, collaboration partners heading clinical trials and registries for BrMet patients, and informaticians who are experts in integrating omics data and developing prediction models. We expect to unravel molecular mechanisms of immune cell infiltration and function in the BrMet TME and to increase the success rate of immunotherapy for BrMet patients.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.