Journal Article

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

Baker, Syed Murtuza, Tibbitt, Christopher A., Willis, Claire, Gaspal, Fabrina, Kennedy, Bethany C., Fiancette, Rémi, Dean, Isaac, Li, Zhi, Tuong, Zewen K., Mjösberg, Jenny, Sexl, Veronika, Dovedi, Simon J., Clatworthy, Menna R., Lee, Colin Y. C., Matei-Rascu, Veronika, Lindforss, Ulrik, Hammond, Scott A., Hepworth, Matthew R., Withers, David R., Carlesso, Gianluca, Stockmann, Christian, Nordenvall, Caroline

2024

Overview

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. Natural killer (NK) cells control tumor growth through direct cytotoxicity and recruitment of other leukocytes. Here, using photoconversion-based labeling to track the fate of NK cells in vivo, the authors demonstrate that loss of NK cell function occurs very rapidly following their entry into tumors, but can be reversed by IL-15 administration.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/31 / 38/91 / 631/250/2504 / 631/67/327 / 64/60 / Biocompatibility / Cytotoxicity / Effector cells / Gene Expression Profiling / Humanities and Social Sciences / Humans / Immune system / Interleukin 15 / Internship and Residency / Killer Cells, Natural / Labeling / Leukocyte migration / multidisciplinary / Natural killer cells / Neoplasms / Science / Science (multidisciplinary) / Transcriptome / Transcriptomics / Tumor Microenvironment / Tumors