Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping

Herman Netskar, Aline Pfefferle, Jodie P. Goodridge, Ebba Sohlberg, Olli Dufva, Sarah A. Teichmann, Demi Brownlie, Jakob Michaëlsson, Nicole Marquardt, Trevor Clancy, Amir Horowitz, Karl Johan Malmberg

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor–ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56bright state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56dim state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions.

Original languageEnglish
Pages (from-to)1445-1459
Number of pages15
JournalNature Immunology
Volume25
Issue number8
DOIs
StatePublished - Aug 2024

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