Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
Radiation Biology Research Center, Institute for Radiologic Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan 333323, Taiwan.
Int J Mol Sci. 2021 Feb 19;22(4):2091. doi: 10.3390/ijms22042091.
The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.
胰腺癌患者的总体生存率较低，这促使研究人员寻求新的治疗方案。放射治疗（RT）经常是胰腺癌新辅助或姑息治疗的选择。本研究探讨了 RT 方案对肿瘤微环境（TME）的影响及其对抗程序性细胞死亡配体-1（PD-L1）治疗的影响。使用 UN-KC-6141 鼠原位胰腺肿瘤模型，通过免疫组织化学染色检查 RT 扰乱的 TME。结果表明，消融性 RT 比分割性 RT 更有效地招募 T 细胞。另一方面，分割性 RT 比消融性 RT 诱导更多的髓系来源抑制细胞浸润。RT 扰乱的 TME 表现出更高的每血管灌注率。血管灌注的增加与更多的抗 PD-L1 抗体被输送到肿瘤有关。消融性 RT 后抗 PD-L1 治疗可提高动物存活率，与对照组中位存活时间为 16.5 天相比，接种肿瘤后超过 30 天存活的治疗动物比例为 67%。从存活动物中分离的脾细胞对 UN-KC-6141 细胞具有特异性细胞毒性。我们得出结论，与常规 RT 诱导的 TME 相比，消融性 RT 诱导的 TME 更适合与免疫检查点阻断联合治疗。
