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Title (en)
Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity
Language
English
Description (en)
Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.
Keywords (en)
Innate Lymphoid-Cells; Cd8(+) T-Cells; Mouse Nk Cells; Growth-Factor; Adaptive Immunity; Dendritic Cells; In-Vivo; Expression; Programs; Differentiation
DOI
10.1038/s41467-024-44789-z
Author of the digital object
Isaac Dean  (University of Birmingham)
Menna R. Clatworthy  (University of Cambridge / Wellcome Genome Campus)
David R. Withers  (University of Birmingham)
Gianluca Carlesso  (AstraZeneca)
Matthew R. Hepworth  (University of Manchester)
Jenny Mjösberg  (Karolinska Institutet / Karolinska University Hospital)
Simon J. Dovedi  (AstraZeneca)
Scott A. Hammond  (AstraZeneca)
Veronika Sexl  (University of Veterinary Medicine Vienna)
Christian Stockmann  (University of Zurich)
Syed Murtuza Baker  (University of Manchester)
Ulrik Lindforss  (Karolinska University Hospital)
Caroline Nordenvall  (Karolinska University Hospital)
Rémi Fiancette  (University of Birmingham)
Veronika Matei-Rascu  (University of Birmingham)
Bethany C. Kennedy  (University of Birmingham)
Fabrina Gaspal  (University of Birmingham)
Claire Willis  (University of Birmingham)
Christopher A. Tibbitt  (Karolinska Institutet)
Zhi Li  (University of Birmingham)
Colin Y. C. Lee  (University of Cambridge / Wellcome Genome Campus)
Zewen K. Tuong  (University of Cambridge / Wellcome Genome Campus)
Format
application/pdf
Size
1.4 MB
Licence Selected
CC BY 4.0 International
Type of publication
Article
Name of Publication (en)
Nature Communications
Pages or Volume
18
Volume
15
Number
1
Publisher
Nature Portfolio
Publication Date
2024