Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity

Isaac Dean, Colin Y. C. Lee, Zewen K. Tuong, Zhi Li, Christopher A. Tibbitt, Claire Willis, Fabrina Gaspal, Bethany C. Kennedy, Veronika Matei-Rascu, Rémi Fiancette, Caroline Nordenvall, Ulrik Lindforss, Syed Murtuza Baker, Christian Stockmann, Veronika Sexl, Scott A. Hammond, Simon J. Dovedi, Jenny Mjösberg, Matthew R. Hepworth, Gianluca Carlesso, Menna R. Clatworthy () and David R. Withers ()
Additional contact information
Isaac Dean: University of Birmingham
Colin Y. C. Lee: University of Cambridge
Zewen K. Tuong: University of Cambridge
Zhi Li: University of Birmingham
Christopher A. Tibbitt: Karolinska Institutet
Claire Willis: University of Birmingham
Fabrina Gaspal: University of Birmingham
Bethany C. Kennedy: University of Birmingham
Veronika Matei-Rascu: University of Birmingham
Rémi Fiancette: University of Birmingham
Caroline Nordenvall: Karolinska Institutet and Department of Pelvic Cancer, Karolinska University Hospital
Ulrik Lindforss: Karolinska Institutet and Department of Pelvic Cancer, Karolinska University Hospital
Syed Murtuza Baker: the University of Manchester, Manchester Academic Health Science Centre
Christian Stockmann: University of Zurich
Veronika Sexl: University of Veterinary Medicine
Scott A. Hammond: Early Oncology R&D
Simon J. Dovedi: Early Oncology R&D
Jenny Mjösberg: Karolinska Institutet
Matthew R. Hepworth: the University of Manchester, Manchester Academic Health Science Centre
Gianluca Carlesso: Early Oncology R&D
Menna R. Clatworthy: University of Cambridge
David R. Withers: University of Birmingham

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44789-z

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