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Radiotherapy transi...
Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity
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- Tuomela, Karoliina (author)
- Univ Manchester, Lydia Becker Inst Immunol & Inflammat, United Kingdom, Manchester M13 9NT, Lancs, England.
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- Mukherjee, Debayan (author)
- Univ Manchester, Div Canc Sci, Manchester M13 9PL, Lancs, England.
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- Ambrose, Ashley R. (author)
- Univ Manchester, Lydia Becker Inst Immunol & Inflammat, United Kingdom, Manchester M13 9NT, Lancs, England.
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- Harikrishnan, Ashish (author)
- Univ Manchester, Lydia Becker Inst Immunol & Inflammat, United Kingdom, Manchester M13 9NT, Lancs, England.
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- Mole, Holly (author)
- Univ Manchester, Lydia Becker Inst Immunol & Inflammat, United Kingdom, Manchester M13 9NT, Lancs, England.
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- Hurlstone, Adam (author)
- Univ Manchester, Lydia Becker Inst Immunol & Inflammat, United Kingdom, Manchester M13 9NT, Lancs, England.
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- Önfelt, Björn (author)
- KTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden.
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- Honeychurch, Jamie (author)
- Univ Manchester, Div Canc Sci, Manchester M13 9PL, Lancs, England.
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- Davis, Daniel M. (author)
- Univ Manchester, Lydia Becker Inst Immunol & Inflammat, United Kingdom, Manchester M13 9NT, Lancs, England.
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Univ Manchester, Lydia Becker Inst Immunol & Inflammat, United Kingdom, Manchester M13 9NT, Lancs, England Univ Manchester, Div Canc Sci, Manchester M13 9PL, Lancs, England. (creator_code:org_t)
- 2022-01-18
- 2022
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:3, s. e2111900119-
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- NK cell
- T cell
- perforin
- cancer
- radiotherapy
Publication and Content Type
- ref (subject category)
- art (subject category)
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