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Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8

Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a reverse translational approach, we show a central role of NK cells in the radiation-induced immune res...

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Main Authors: Walle, Thomas (Author) , Kraske, Joscha (Author) , Liao, Boyu (Author) , Lenoir, Bénédicte (Author) , Timke, Carmen (Author) , Halbach, Emilia von Bohlen Und (Author) , Tran, Florian (Author) , Griebel, Paul (Author) , Albrecht, Dorothee (Author) , Ahmed, Azaz (Author) , Suarez-Carmona, Meggy (Author) , Jimenez-Sanchez, Alejandro (Author) , Beikert, Tizian (Author) , Tietz-Dahlfuss, Alexandra (Author) , Menevse, Ayse Nur (Author) , Schmidt, Gabriele (Author) , Brom, Manuela (Author) , Pahl, Jens (Author) , Antonopoulos, Wiebke (Author) , Miller, Matthias (Author) , Lopez Perez, Ramon (Author) , Bestvater, Felix (Author) , Giese, Nathalia (Author) , Beckhove, Philipp (Author) , Rosenstiel, Philip (Author) , Jäger, Dirk (Author) , Strobel, Oliver (Author) , Pe'er, Dana (Author) , Halama, Niels (Author) , Debus, Jürgen (Author) , Cerwenka, Adelheid (Author) , Huber, Peter E. (Author)
Format: Article (Journal)
Language:English
Published: 23 Mar 2022
In: Science advances
Year: 2022, Volume: 8, Issue: 12, Pages: 1-19
ISSN:2375-2548
DOI:10.1126/sciadv.abh4050
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1126/sciadv.abh4050
Verlag, kostenfrei, Volltext: https://www.science.org/doi/10.1126/sciadv.abh4050
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Author Notes:Thomas Walle, Joscha A. Kraske, Boyu Liao, Bénédicte Lenoir, Carmen Timke, Emilia von Bohlen und Halbach, Florian Tran, Paul Griebel, Dorothee Albrecht, Azaz Ahmed, Meggy Suarez-Carmona, Alejandro Jiménez-Sánchez, Tizian Beikert, Alexandra Tietz-Dahlfuss, Ayse Nur Menevse, Gabriele Schmidt, Manuela Brom, Jens H. W. Pahl, Wiebke Antonopoulos, Matthias Miller, Ramon Lopez Perez, Felix Bestvater, Nathalia A. Giese, Philipp Beckhove, Philip Rosenstiel, Dirk Jäger, Oliver Strobel, Dana Pe'er, Niels Halama, Jürgen Debus, Adelheid Cerwenka, Peter E. Huber

MARC

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520 |a Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a reverse translational approach, we show a central role of NK cells in the radiation-induced immune response involving a CXCL8/IL-8-dependent mechanism. In a randomized controlled pancreatic cancer trial, CXCL8 increased under radiotherapy, and NK cell positively correlated with prolonged overall survival. Accordingly, NK cells preferentially infiltrated irradiated pancreatic tumors and exhibited CD56(dim)-like cytotoxic transcriptomic states. In experimental models, NF-kappa B and mTOR orchestrated radiation-induced CXCL8 secretion from tumor cells with senescence features causing directional migration of CD56(dim) NK cells, thus linking senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined high-dose radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice, suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy. 
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