and PCT/EP2016/057355 applied for by Spatial Transcriptomics AB (10x Genomics) covering the described technology. M.R. is employed by Illumina Inc. A.R. is a founder and equity holder of Celsius Therapeutics and an SAB member of Syros Pharmaceuticals and Thermo Fisher Scientific.Reporting summary: Further information on research design is available in the Life Sciences Reporting Summary linked to this article. Data availability:The raw mouse data have been deposited to NCBI's GEO archive GSE130682. Raw files for the breast cancer sample are available through an MTA with Åke Borg

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In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases.