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

Author

Listed:
  • Isaac Dean

    (University of Birmingham)

  • Colin Y. C. Lee

    (University of Cambridge
    Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton)

  • Zewen K. Tuong

    (University of Cambridge
    Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton)

  • 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
    Clinical Lung and Allergy Research, Medical unit for Lung and Allergy Diseases, Karolinska University Hospital)

  • Matthew R. Hepworth

    (the University of Manchester, Manchester Academic Health Science Centre)

  • Gianluca Carlesso

    (Early Oncology R&D)

  • Menna R. Clatworthy

    (University of Cambridge
    Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton)

  • David R. Withers

    (University of Birmingham)

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.

Suggested Citation

  • 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 & Ul, 2024. "Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44789-z
    DOI: 10.1038/s41467-024-44789-z
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    2. Paula A. Clark & Mayuri Gogoi & Noe Rodriguez-Rodriguez & Ana C. F. Ferreira & Jane E. Murphy & Jennifer A. Walker & Alastair Crisp & Helen E. Jolin & Jacqueline D. Shields & Andrew N. J. McKenzie, 2024. "Recipient tissue microenvironment determines developmental path of intestinal innate lymphoid progenitors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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