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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-09-01

AUTHORS

Bettina Weigelin, Annemieke Th. den Boer, Esther Wagena, Kelly Broen, Harry Dolstra, Rob J. de Boer, Carl G. Figdor, Johannes Textor, Peter Friedl

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. More... »

PAGES

5217

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41467-021-25282-3

DOI

http://dx.doi.org/10.1038/s41467-021-25282-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1140804136

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/34471116


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