Radiation-Induced Innate Neutrophil Response in Tumor Is Mediated by the CXCLs/CXCR2 Axis

Authors

Faya Zhang
Oscar Mulvaney
Erica Salcedo
Subrata Manna
James Z Zhu
Tao Wang
Chul Ahn
Laurentiu M Pop
Raquibul Hannan

Language

English

Publication Date

12-1-2023

Journal

Cancers

DOI

10.3390/cancers15235686

PMID

38067390

PMCID

PMC10705172

PubMedCentral® Posted Date

12-1-2023

PubMedCentral® Full Text Version

Post-print

Abstract

The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is an early innate inflammatory response that occurs within 24-48 h. Using two different syngeneic murine tumor models (RM-9 and MC-38), we demonstrated that CXCR2 blockade significantly reduced RT-induced neutrophilic infiltration. CXCR2 blockade showed the same effects on RT-induced tumor inhibition and host survival as direct neutrophil depletion. Neutrophils highly and preferentially expressed CXCR2 compared to other immune cells. Importantly, RT induced both gene and protein expression of CXCLs in the TME within 24 h, attracting neutrophils into the tumor. Expectedly, RT also upregulated the gene expression of both cGAS and AIM2 DNA-sensing pathways in cGAS-positive MC-38 tumors but not in cGAS-negative RM-9 tumors. Activation of these pathways resulted in increased IL-1β, which is known to activate the CXCLs/CXCR2 axis. Gene ontology analysis of mRNA-Seq supported these findings. Taken together, the findings suggest that the CXCLs/CXCR2 axis mediates the RT-induced innate inflammatory response in the TME, likely translating the effects of innate DNA-sensing pathways that are activated in response to RT-induced DNA damage.

Keywords

CXCLs, CXCR2, radiation therapy, IL-1β, neutrophils, DNA sensing, tumor microenvironment

Published Open-Access

yes

Recommended Citation

Zhang, Faya; Mulvaney, Oscar; Salcedo, Erica; et al., "Radiation-Induced Innate Neutrophil Response in Tumor Is Mediated by the CXCLs/CXCR2 Axis" (2023). Faculty, Staff and Student Publications. 6745.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6745