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

B Weigelin, AT den Boer, E Wagena, K Broen… - Nature …, 2021 - nature.com
B Weigelin, AT den Boer, E Wagena, K Broen, H Dolstra, RJ de Boer, CG Figdor, J Textor
Nature communications, 2021nature.com
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 …
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.
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