Radiation therapy (RT) is used in the management of several cancers; however, tumor radioresistance remains a challenge. Polymorphonuclear neutrophils (PMNs) are recruited to the tumor immune microenvironment (TIME) post-RT and can facilitate tumor progression by forming neutrophil extracellular traps (NETs).
Here, we demonstrate a role for NETs as players in tumor radioresistance. Using a syngeneic bladder cancer model, increased NET deposition is observed in the TIME of mice treated with RT and inhibition of NETs improves overall radiation response. In vitro, the protein HMGB1 promotes NET formation through a TLR4-dependent manner and in vivo, inhibition of both HMGB1 and NETs significantly delays tumor growth. Finally, NETs are observed in bladder tumors of patients who did not respond to RT and had persistent disease post-RT, wherein a high tumoral PMN-to-CD8 ratio is associated with worse overall survival. Together, these findings identify NETs as a potential therapeutic target to increase radiation efficacy.
Nature communications. 2021 May 13*** epublish ***
Surashri Shinde-Jadhav, Jose Joao Mansure, Roni F Rayes, Gautier Marcq, Mina Ayoub, Rodrigo Skowronski, Ronald Kool, France Bourdeau, Fadi Brimo, Jonathan Spicer, Wassim Kassouf
Urologic Oncology Research Division, McGill University Health Centre, Montreal, Canada., Division of Thoracic Surgery, McGill University Health Centre, Montreal, Canada., Department of Pathology, McGill University Health Center, Montreal, Canada., Department of Surgery, Faculty of Medicine, McGill University, Montreal, Canada. ., Urologic Oncology Research Division, McGill University Health Centre, Montreal, Canada. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/33986291