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@article{Tuomela:2022:10.1073/pnas.2111900119,
author = {Tuomela, K and Mukherjee, D and Ambrose, AR and Harikrishnan, A and Mole, H and Hurlstone, A and Onfelt, B and Honeychurch, J and Davis, DM},
doi = {10.1073/pnas.2111900119},
journal = {Proceedings of the National Academy of Sciences of USA},
title = {Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity},
url = {http://dx.doi.org/10.1073/pnas.2111900119},
volume = {119},
year = {2022}
}
TY - JOUR
AB - The impact of radiotherapy on the interaction between immune cells and cancer cells is important not least because radiotherapy can be used alongside immunotherapy as a cancer treatment. Unexpectedly, we found that X-ray irradiation of cancer cells induced significant resistance to natural killer (NK) cell killing. This was true across a wide variety of cancer-cell types as well as for antibody-dependent cellular cytotoxicity. Resistance appeared 72 h postirradiation and persisted for 2 wk. Resistance could also occur independently of radiotherapy through pharmacologically induced cell-cycle arrest. Crucially, multiple steps in NK-cell engagement, synapse assembly, and activation were unaffected by target cell irradiation. Instead, radiotherapy caused profound resistance to perforin-induced calcium flux and lysis. Resistance also occurred to a structurally similar bacterial toxin, streptolysin O. Radiotherapy did not affect the binding of pore-forming proteins at the cell surface or membrane repair. Rather, irradiation instigated a defect in functional pore formation, consistent with phosphatidylserine-mediated perforin inhibition. In vivo, radiotherapy also led to a significant reduction in NK cell–mediated clearance of cancer cells. Radiotherapy-induced resistance to perforin also constrained chimeric antigen receptor T-cell cytotoxicity. Together, these data establish a treatment-induced resistance to lymphocyte cytotoxicity that is important to consider in the design of radiotherapy–immunotherapy protocols.
AU - Tuomela,K
AU - Mukherjee,D
AU - Ambrose,AR
AU - Harikrishnan,A
AU - Mole,H
AU - Hurlstone,A
AU - Onfelt,B
AU - Honeychurch,J
AU - Davis,DM
DO - 10.1073/pnas.2111900119
PY - 2022///
SN - 0027-8424
TI - Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity
T2 - Proceedings of the National Academy of Sciences of USA
UR - http://dx.doi.org/10.1073/pnas.2111900119
VL - 119
ER -
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