Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8
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 N. Menevse, Gabriele Schmidt, Manuela Brom, Jens 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
Abstract
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-κB 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.