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.
| Original language | English |
|---|---|
| Article number | 5217 |
| Pages (from-to) | 1-12 |
| Journal | Nature Communications |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Dec 2021 |
Bibliographical note
Funding Information:We thank Stephen P. Schoenberger for providing the MEC-1/OVA cell line. pCDH-NLS-copGFP-EF1-BlastiS was a gift from Jan Lammerding (Addgene plasmid #132772). This work was supported by the Dutch Cancer Foundation (KWF 2008-4031) to C.G.F. and P.F., a personal KWF grant to A.Th.d.B.), NWO-Rubicon (019.162LW.020) to B.W., the FP7 of the European Union (ENCITE HEALTH TH-15-2008-208142), NWO-VICI (918.11.626), the European Research Council (617430-DEEPINSIGHT), and the Cancer Genomics Cancer, The Netherlands to P.F. Time-lapse confocal microscopy was enabled by an NWO investment grant (834.13.003).
Publisher Copyright:
© 2021, The Author(s).
Funding
We thank Stephen P. Schoenberger for providing the MEC-1/OVA cell line. pCDH-NLS-copGFP-EF1-BlastiS was a gift from Jan Lammerding (Addgene plasmid #132772). This work was supported by the Dutch Cancer Foundation (KWF 2008-4031) to C.G.F. and P.F., a personal KWF grant to A.Th.d.B.), NWO-Rubicon (019.162LW.020) to B.W., the FP7 of the European Union (ENCITE HEALTH TH-15-2008-208142), NWO-VICI (918.11.626), the European Research Council (617430-DEEPINSIGHT), and the Cancer Genomics Cancer, The Netherlands to P.F. Time-lapse confocal microscopy was enabled by an NWO investment grant (834.13.003).
