Lena Jassowicz, Fangyoumin Feng, Rolf Warta, Fatima Heinicke, Amélie Wöllner, Hannah Briesch, Furkan Sor, Julia Soller, Catharina Lotsch, John K.L. Wong, Chang-Gyun Park, Nicolas Aubert, Maximilian Scheer, Zhaoqing Hu, Maximilian Knoll, Julian Schlegel, Lukas Frank, Philip Dao Trong, Gerhard Jungwirth, Amin Nohman, Kendra Maaß, Niels Grabe, Mandy Barthel, Simone Butz, Christina Lulay, Manuela Zucknick, Michele Bortolomeazzi, Pooja Sant, Verena Thewes, Laura Michel, Carlo Fremd, Andreas Schneeweiss, Chong Sun, Karsten Rippe, Amir Abdollahi, Andreas von Deimling, Andreas Unterberg, Sandro M. Krieg, Jan‐Philipp Mallm, Peter Lichter, Marc Zapatka, Martina Seiffert, Christel Herold-Mende
Breast cancer brain metastases (BCBM) are a severe condition with high demand for improved personalized treatment, but a comprehensive understanding of BCBM immune-microenvironment heterogeneity and susceptibility to immunotherapy is lacking. Here, we multimodally profile the immune niche in a clinically well-annotated cohort of 156 BCBM applying tissue cytometry, bulk and single nuclei RNA-sequencing, flow cytometry, and spatial transcriptomics, complemented by functional studies in patient-derived models. Integrative analyses reveal two immune landscapes predicting prolonged patient survival and that are not deducible from paired primary tumors: 1) BCBM with a high proportion of CD8 + tissue-resident-like memory T cells as major players of tumor immune control. 2) BCBM containing tertiary lymphoid structures. Surrogate signatures of these landscapes are prognostic in independent BCBM and primary breast cancer cohorts, are associated with fewer metastases, and predict immunotherapy response. Our work provides critical insights into anti-tumor immunity in BCBM and identifies novel biomarkers with translational relevance.