期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：3
DOI：10.1073/pnas.2111900119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Radiotherapy is one of the most common forms of cancer treatment used today. Its impact in directly killing cancer cells, and on antitumour immunity, is well recognized, but its effect on immune cell–cancer cell interactions is not fully understood. Here, we show that irradiation of cancer cells surprisingly leads to resistance against immune cell cytotoxicity. This was mediated by a reduced susceptibility to the pore-forming protein perforin. Resistance manifested as a reduction in both necrotic death following osmotic lysis and apoptotic death following granzyme B uptake. Overall, these data establish a form of treatment-induced resistance to lymphocyte cytotoxicity. These findings have significant implications for the optimal design of radiotherapy–immunotherapy protocols.
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.
