Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8

Media type: E-Article

Title: Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8

Contributor: 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]

Published: 23 Mar 2022

Language: English

DOI: 10.1126/sciadv.abh4050

Identifier:

Keywords: mice ; colorectal-cancer ; growth ; interleukin-8 ; nf-kappa-b ; nk ; progression ; secretory phenotype ; senescence ; t-cell

Origination:

Footnote:

Description: 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.

Access State: Open Access

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