Periodic Reporting for period 1 - cellsIMPACT (Understanding resistance to immune checkpoint inhibitors by mapping the tumor-host ecosystem at single-cell resolution)
Okres sprawozdawczy: 2020-05-01 do 2022-04-30
Applying various bioinformatic and statistical approaches to scRNA-seq data we established a comprehensive view of the cellular architecture of the melanoma ecosystem, and defined 6 evolutionarily conserved melanoma transcriptional metaprograms (Melanocytic, Mesenchymal-like, Neural Crest-like, Antigen Presentation, Stress (hypoxia response) and Stress (p53 response). Our results suggest that these metaprograms are not solely driven by genetic makeup. Instead, we postulate that they are partly driven by specific cell-cell interactions with the tumour microenvironment. This was consistent with a non-random geographical distribution of the melanoma cell states as revealed by spatial transcriptomic analyses. Importantly, two of the metaprograms were associated with divergent clinical responses to ICB. While the Antigen Presentation cell population was more abundant in tumours from patients who exhibited a clinical response to ICB, Mesenchymal-like cells were significantly enriched in early on-treatment biopsies from non-responders, and their presence significantly predicted lack of response. Critically, we identified TCF4 (E2-2) as a master regulator of the Mesenchymal-like program. Targeting TCF4 expression in Mesenchymal-like cells either genetically or pharmacologically using a bromodomain inhibitor increased immunogenicity and sensitivity to targeted therapy.
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