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

Published version
Peer-reviewed

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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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Keywords

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

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

15

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MR/S035842/1)
Wellcome Trust (220268/Z/20/Z)