Decoupling T cell cytotoxicity: a CCL21+ICAM1-based synthetic immune niche enhances tumor elimination by accelerating lytic hit delivery.
6 affiliations
- 1Center for Interdisciplinary Digital Sciences, Department Information Services and High Performance Computing, TUD Dresden University of Technology, Dresden, Germany. [email protected].
- 2Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
- 3Center for Interdisciplinary Digital Sciences, Department Information Services and High Performance Computing, TUD Dresden University of Technology, Dresden, Germany.
- 4Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. [email protected].
- 5Department of Mathematics, Khalifa University, Abu Dhabi, UAE.
- 6Health and Life Sciences, European University Cyprus at Frankfurt, Frankfurt, Germany.
Abstract
Preserving T cell cytotoxic function during ex vivo expansion remains a major challenge for adoptive cancer immunotherapy. A synthetic immune niche (SIN) composed of immobilized CCL21 and ICAM1 was shown to improve T cell expansion while preserving cytotoxicity; however, it remains unclear which specific step of the T cell killing process is enhanced by the SIN stimulation. Here, we combined advanced imaging based on time-lapse microscopy with a mean-field model to analyze the distinct stages in killing of B16 melanoma cells by CD8[Formula: see text] T cells. This framework enabled us to resolve the tumor cell killing process into discrete steps throughout target cell engagement with SIN-treated T cells and lytic hit delivery. We found that tumor cell death is best explained by a multi-hit process, requiring approximately four discrete hits to trigger cell death. Model-based analysis identified a significant increase in the lytic hit-delivery rate, [Formula: see text], as the main kinetic change associated with the enhanced cytotoxicity of SIN-treated T cells. The target encounter rate, [Formula: see text], could not be reliably compared between conditions because it was practically non-identifiable in the untreated dataset. Global sensitivity analysis further showed that increasing lytic hit delivery has a stronger effect on tumour control than increasing target encounter rates. These findings fundamentally reorient our understanding of optimized T cell manufacturing, suggesting that the lytic execution step may be the primary rate-limiting bottleneck in this in-vitro system, and that engineering strategies targeting granule polarization or discharge warrant prioritization alongside affinity-enhancement approaches.
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BibTeX
@article{gupta2026decoupling,
title = {{Decoupling T cell cytotoxicity: a CCL21+ICAM1-based synthetic immune niche enhances tumor elimination by accelerating lytic hit delivery.}},
author = {Manish Kumar Gupta and Rawan Zoabi and Sofi Yado and Jörn Starruß and Benjamin Geiger and Haralampos Hatzikirou},
journal = {BMC cancer},
year = {2026},
month = oct,
doi = {10.1186/s12885-026-16748-y},
url = {https://europepmc.org/article/MED/42875767},
note = {CC BY},
}
RIS
TY - JOUR
TI - Decoupling T cell cytotoxicity: a CCL21+ICAM1-based synthetic immune niche enhances tumor elimination by accelerating lytic hit delivery.
AU - Manish Kumar Gupta
AU - Rawan Zoabi
AU - Sofi Yado
AU - Jörn Starruß
AU - Benjamin Geiger
AU - Haralampos Hatzikirou
PY - 2026
DA - 2026/10/15
JO - BMC cancer
DO - 10.1186/s12885-026-16748-y
UR - https://europepmc.org/article/MED/42875767
AB - Preserving T cell cytotoxic function during ex vivo expansion remains a major challenge for adoptive cancer immunotherapy. A synthetic immune niche (SIN) composed of immobilized CCL21 and ICAM1 was shown to improve T cell expansion while preserving cytotoxicity; however, it remains unclear which specific step of the T cell killing process is enhanced by the SIN stimulation. Here, we combined advanced imaging based on time-lapse microscopy with a mean-field model to analyze the distinct stages in killing of B16 melanoma cells by CD8[Formula: see text] T cells. This framework enabled us to resolve the tumor cell killing process into discrete steps throughout target cell engagement with SIN-treated T cells and lytic hit delivery. We found that tumor cell death is best explained by a multi-hit process, requiring approximately four discrete hits to trigger cell death. Model-based analysis identified a significant increase in the lytic hit-delivery rate, [Formula: see text], as the main kinetic change associated with the enhanced cytotoxicity of SIN-treated T cells. The target encounter rate, [Formula: see text], could not be reliably compared between conditions because it was practically non-identifiable in the untreated dataset. Global sensitivity analysis further showed that increasing lytic hit delivery has a stronger effect on tumour control than increasing target encounter rates. These findings fundamentally reorient our understanding of optimized T cell manufacturing, suggesting that the lytic execution step may be the primary rate-limiting bottleneck in this in-vitro system, and that engineering strategies targeting granule polarization or discharge warrant prioritization alongside affinity-enhancement approaches.
SN - 1471-2407
ER -