Zhang Faya, Mulvaney Oscar, Salcedo Erica, Manna Subrata, Zhu James Z, Wang Tao, Ahn Chul, Pop Laurentiu M, Hannan Raquibul
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cancers (Basel). 2023 Dec 1;15(23):5686. doi: 10.3390/cancers15235686.
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.
放疗（RT）在激活先天性DNA传感通路的DNA损伤反应后，在肿瘤微环境（TME）中引发炎症和免疫调节作用的早期事件在很大程度上尚不清楚。放疗后中性粒细胞浸润到TME中是一种在24 - 48小时内发生的早期先天性炎症反应。使用两种不同的同基因小鼠肿瘤模型（RM - 9和MC - 38），我们证明CXCR2阻断显著减少了放疗诱导的中性粒细胞浸润。CXCR2阻断对放疗诱导的肿瘤抑制和宿主存活的影响与直接清除中性粒细胞相同。与其他免疫细胞相比，中性粒细胞高度且优先表达CXCR2。重要的是，放疗在24小时内诱导了TME中CXCLs的基因和蛋白表达，吸引中性粒细胞进入肿瘤。不出所料，放疗还上调了cGAS阳性的MC - 38肿瘤中cGAS和AIM2 DNA传感通路的基因表达，但在cGAS阴性的RM - 9肿瘤中未上调。这些通路的激活导致IL - 1β增加，已知IL - 1β会激活CXCLs/CXCR2轴。mRNA测序的基因本体分析支持了这些发现。综上所述，这些发现表明CXCLs/CXCR2轴介导了放疗在TME中诱导的先天性炎症反应，可能转化了因放疗诱导的DNA损伤而激活的先天性DNA传感通路的作用。
