IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-25282-3.html
   My bibliography  Save this article

Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity

Author

Listed:
  • Bettina Weigelin

    (Radboud University Medical Center
    The University of Texas MD Anderson Cancer Center
    Eberhard Karls University
    University of Tuebingen)

  • Annemieke Th. Boer

    (Maastricht University)

  • Esther Wagena

    (Radboud University Medical Center)

  • Kelly Broen

    (Radboud University Medical Center)

  • Harry Dolstra

    (Radboud University Medical Center)

  • Rob J. Boer

    (Utrecht University)

  • Carl G. Figdor

    (Radboud University Medical Centre)

  • Johannes Textor

    (Radboud University Medical Centre)

  • Peter Friedl

    (Radboud University Medical Center
    The University of Texas MD Anderson Cancer Center
    Cancer Genomics Centre Netherlands (CGC.nl))

Abstract

Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, “yes/no” process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of “additive cytotoxicity” by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy.

Suggested Citation

  • Bettina Weigelin & Annemieke Th. Boer & Esther Wagena & Kelly Broen & Harry Dolstra & Rob J. Boer & Carl G. Figdor & Johannes Textor & Peter Friedl, 2021. "Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25282-3
    DOI: 10.1038/s41467-021-25282-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-25282-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-25282-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25282-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.