Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity

Karoliina Tuomela, Debayan Mukherjee, Ashley Ambrose, Ashish Harikrishnan, Holly Mole, Adam Hurlstone, Björn Önfelt, Jamie Honeychurch, Daniel M Davis

Research output: Contribution to journalArticlepeer-review


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 hours post-irradiation and persisted for two weeks. 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. Moreover, radiotherapy-induced resistance to perforin also constrained CAR T cell cytotoxicity. Overall, these data establish a treatment-induced resistance to lymphocyte cytotoxicity that is important to consider in the design of radiotherapy-immunotherapy protocols.
Original languageEnglish
JournalProceedings of the National Academy of Sciences
Publication statusAccepted/In press - 16 Dec 2021


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