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

Bettina Weigelin (), Annemieke Th. Boer, Esther Wagena, Kelly Broen, Harry Dolstra, Rob J. Boer, Carl G. Figdor, Johannes Textor and Peter Friedl ()
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Bettina Weigelin: Radboud University Medical Center
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

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25282-3

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