An integrated single-cell atlas of checkpoint inhibitor-induced liver injury links shared liver-tumour CD8+ T cell clones to cytotoxicity and macrophage crosstalks
Uzun, S.; Haefliger, S.; Zinner, C. P.; Pant, A.; Beenen, A.; Bendik, N.; Heusler, H.; Stalder, A. K.; Whipman, J.; Mertz, K. D.; Vosbeck, J.; Zippelius, A.; Heim, M. H.; de Souza, N.; Bernsmeier, C.; Läubli, H.; Bodenmiller, B.; Matter, M. S.
Show abstract
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, but they can also induce immune-related adverse events (irAEs). Checkpoint inhibitor-induced liver injury (ChILI) is among the most frequent irAEs, yet its pathophysiology remains poorly understood. Here, we assembled a cohort of liver biopsies from cancer patients with ChILI and used a multi-modal analysis integrating single-cell spatial proteomics, bulk T cell receptor (TCR) sequencing and single-cell spatial transcriptomics to construct the first single-cell spatial atlas of ChILI. Integrating bulk and spatial TCR analyses revealed expanded T cell clones with a cytotoxic CD8+ phenotype that were shared between the liver and tumour. Intercellular communication analyses further indicated close interactions between the shared T cell clones and macrophages involving CCL5-CCR1 signalling. Our work provides in situ evidence of tumour-associated T cell contributions to ChILI. Furthermore, it establishes a framework for gaining mechanistic insights into ChILI and identifying therapeutic targets.
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