Advancing spatial transcriptomics through dissociative tissue analysis in plasma cell dyscrasias 4559

Abstract Description Plasma cell dyscrasias (PCDs) rely on complex tumor microenvironment (TME) architectures to evade immune responses and therapeutic interventions. While advances in spatial technologies have enhanced our understanding of these subcellular networks, limitations like low transcriptomic resolution and poor segmentation in highly proliferative sections hinder accurate identification of tumor and immune cell types in tissue sections. To address this, we applied spatial transcriptomics (ST) and single-cell Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) to formalin-fixed paraffin-embedded (FFPE) blocks of preserved extramedullary soft tissue and bone marrow samples [n = 20] from patients diagnosed with multiple myeloma or other PCDs. We created a multimodal reference for PCDs, highlighting distinct tumor states and immune niches in the surrounding TME. By projecting low-dimensional ST data onto higher-dimensional CITE-seq data, we improved cell typing, pathway analyses and gene panel design; enabling robust downstream analyses of our ST data. Using these approaches we uncovered key insights into the contributions of tissue-resident natural killer cells and cytotoxic T cells to anti-tumor responses. Importantly, we identified spatially resolved immune niches and signaling pathways within the TME that could serve as potential therapeutic targets, underscoring the power of integrating tissue-specific single-cell technologies with spatial transcriptomics. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)