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

Cytotoxic CD8(+) T lymphocytes (CTL) often fail to kill tumour cells in one-to-one interactions. Here the authors show that these sublethal interactions from multiple CTL can add up over time and achieve tumour cell killing by additive cytotoxicity. 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.

Automated summary

The study demonstrates that sublethal interactions from multiple CTL can accumulate over time and achieve tumor cell killing by additive cytotoxicity. Statistical modeling reveals that delivering three serial hits within decay intervals below 50 minutes can distinguish between tumor cell death or survival after recovery.