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; David R Withers

doi:10.1038/s41467-024-44789-z

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 CarlessoMenna R Clatworthy^*, David R Withers^*

^*Corresponding author for this work

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	683
Number of pages	18
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-44789-z
Publication status	Published - 24 Jan 2024

Bibliographical note

Keywords

Humans
Neoplasms
Gene Expression Profiling
Internship and Residency
Killer Cells, Natural
Transcriptome
Tumor Microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-44789-zLicence: Creative Commons: Attribution (CC BY)

DeanI2024RapidFinal published version, 4.99 MBLicence: Creative Commons: Attribution (CC BY)

Revealing anti-tumour T cell recruitment and recirculation in vivo to optimise therapeutic intervention.
Withers, D. (Principal Investigator)
Cancer Research Uk
1/02/19 → 31/01/22
Project: Research
ILC3 control of adaptive immune responses
Withers, D. (Principal Investigator)
The Wellcome Trust
1/04/16 → 30/09/21
Project: Research

Cite this

Dean, I., Lee, C. Y. C., Tuong, Z. K., Li, Z., Tibbitt, C. A., Willis, C., Gaspal, F., Kennedy, B. C., Matei-Rascu, V., Fiancette, R., Nordenvall, C., Lindforss, U., Baker, S. M., Stockmann, C., Sexl, V., Hammond, S. A., Dovedi, S. J., Mjösberg, J., Hepworth, M. R., ... Withers, D. R. (2024). Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity. Nature Communications, 15(1), Article 683. https://doi.org/10.1038/s41467-024-44789-z

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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.",

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Dean, I, Lee, CYC, Tuong, ZK, Li, Z, Tibbitt, CA, Willis, C, Gaspal, F, Kennedy, BC, Matei-Rascu, V, Fiancette, R, Nordenvall, C, Lindforss, U, Baker, SM, Stockmann, C, Sexl, V, Hammond, SA, Dovedi, SJ, Mjösberg, J, Hepworth, MR, Carlesso, G, Clatworthy, MR & Withers, DR 2024, 'Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity', Nature Communications, vol. 15, no. 1, 683. https://doi.org/10.1038/s41467-024-44789-z

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AU - Dean, Isaac

AU - Lee, Colin Y C

AU - Tuong, Zewen K

AU - Li, Zhi

AU - Tibbitt, Christopher A

AU - Willis, Claire

AU - Gaspal, Fabrina

AU - Kennedy, Bethany C

AU - Matei-Rascu, Veronika

AU - Fiancette, Rémi

AU - Nordenvall, Caroline

AU - Lindforss, Ulrik

AU - Baker, Syed Murtuza

AU - Stockmann, Christian

AU - Sexl, Veronika

AU - Hammond, Scott A

AU - Dovedi, Simon J

AU - Mjösberg, Jenny

AU - Hepworth, Matthew R

AU - Carlesso, Gianluca

AU - Clatworthy, Menna R

AU - Withers, David R

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N2 - 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.

AB - 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.

KW - Humans

KW - Neoplasms

KW - Gene Expression Profiling

KW - Internship and Residency

KW - Killer Cells, Natural

KW - Transcriptome

KW - Tumor Microenvironment

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DO - 10.1038/s41467-024-44789-z

M3 - Article

C2 - 38267402

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 683

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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Projects

Revealing anti-tumour T cell recruitment and recirculation in vivo to optimise therapeutic intervention.

ILC3 control of adaptive immune responses

Cite this