Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity
| Autor: | Karoliina Tuomela, Debayan Mukherjee, Ashley R. Ambrose, Ashish Harikrishnan, Holly Mole, Adam Hurlstone, Björn Önfelt, Jamie Honeychurch, Daniel M. Davis |
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| Rok vydání: | 2022 |
| Předmět: |
Cytotoxicity
Immunologic Receptors Chimeric Antigen Multidisciplinary Radiotherapy Perforin Cell Membrane Antibody-Dependent Cell Cytotoxicity Receptors Antigen T-Cell T cell Biological Sciences Killer Cells Natural Immunology and Inflammation Bacterial Proteins Cell Line Tumor Neoplasms Streptolysins Humans cancer NK cell Immunotherapy |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2111900119 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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