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.
放射治疗（RT）通过激活先天DNA感知通路引发DNA损伤反应后，在肿瘤微环境（TME）中产生炎症及免疫调节效应的早期机制尚不明确。RT诱导的中性粒细胞浸润是发生在24-48小时内的早期先天炎症反应。通过两种同源小鼠肿瘤模型（RM-9和MC-38），我们发现CXCR2阻断能显著减少RT诱导的中性粒细胞浸润。CXCR2阻断对RT诱导的肿瘤抑制和宿主生存的影响与直接清除中性粒细胞效果相当。相较于其他免疫细胞，中性粒细胞高度且优先表达CXCR2。值得注意的是，RT在24小时内诱导TME中CXCLs基因和蛋白表达上调，从而吸引中性粒细胞浸润肿瘤。如预期所示，RT在cGAS阳性的MC-38肿瘤中上调cGAS和AIM2两种DNA感知通路的基因表达，而在cGAS阴性的RM-9肿瘤中无此效应。这些通路的激活导致IL-1β增加，而IL-1β已知可激活CXCLs/CXCR2轴。mRNA测序的基因本体分析支持这些发现。综上所述，研究结果表明CXCLs/CXCR2轴介导了RT诱导的TME先天炎症反应，这可能是将RT诱导DNA损伤激活的先天DNA感知通路效应转化为炎症反应的关键机制。
Radiation-Induced Innate Neutrophil Response in Tumor Is Mediated by the CXCLs/CXCR2 Axis
肿瘤(癌症)患者之家