Article ; Online: Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity.
Proceedings of the National Academy of Sciences of the United States of America
2022 Volume 119, Issue 3
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Antibody-Dependent Cell Cytotoxicity ; Bacterial Proteins ; Cell Line, Tumor ; Cell Membrane/metabolism ; Cytotoxicity, Immunologic ; Humans ; Immunotherapy ; Killer Cells, Natural/immunology ; Neoplasms/metabolism ; Perforin/metabolism ; Radiotherapy ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/metabolism ; Streptolysins | |||||
| Chemical Substances | Bacterial Proteins ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Streptolysins ; streptolysin O ; Perforin (126465-35-8) | |||||
| Language | English | |||||
| Publishing date | 2022-01-19 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 209104-5 | |||||
| ISSN | 1091-6490 ; 0027-8424 | |||||
| ISSN (online) | 1091-6490 | |||||
| ISSN | 0027-8424 | |||||
| DOI | 10.1073/pnas.2111900119 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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