Using spatial genomics to interrogate tumour clones and the microenvironment in chronic lymphocytic leukaemia (360G-Wellcome-227000_Z_23_Z)

Background Tumour cells evolve by acquiring a diverse repertoire of copy number variants, large chromosomal rearrangements and DNA mutations, leading to clonal diversity. Tumour-infiltrating T-cells, a critical component of the tumour microenvironment, control the growth of clonal cells naturally and in response to treatments such as immunotherapy. Despite its importance, an integrated view of the phenotypic and spatial co-evolution of clonal and tumour infiltrating T-cells has been unexplored. Slide-seq is a novel foundational platform for multi-omic spatial tissue analysis. The resolution, sensitivity and flexibility of the platform now allows for an integrated spatial map of DNA, RNA and now T-cell receptor sequences (TCRs) in human tissue. Chronic lymphocytic leukaemia (CLL), a common and incurable haematological malignancy, is an excellent model for the study of the spatial co-evolution of tumour clones and the microenvironment. Aims 1\. Develop- tumour-specific mutation profiling with Slide-seq. 2\. Generate a computational platform for spatial-omic data integration. 3\. Determine the co-localisation patterns of tumour clones and T-cells in lymph node biopsies in CLL and Richter’s transformation. Outcome Completion of these objectives should advance our understanding of the interactions between tumour and host immunity. This will inform our understanding of cancer progression and potentially on novel microenvironment-directed therapies.