Wang Ying, Shen Na, Wang Yue, Li Mo, Zhang Wanze, Fan Liwen, Liu Linlin, Tang Zhaohui, Chen Xuesi
Department of Radiotherapy, The Second Hospital of Jilin University, Changchun 130041, PR China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
Biomater Sci. 2021 Apr 21;9(8):3019-3027. doi: 10.1039/d1bm00112d. Epub 2021 Mar 3.
The abscopal effect of radiation therapy (RT) is clinically significant but occurs rarely. Although anti-programmed cell death protein 1 antibody (anti-PD1) is likely to enhance the abscopal effect in patients receiving RT, the incidence rate remains less than 30%. One major limitation is the paucity of CD8 T cells within non-irradiated tumors. Here, cisplatin (CDDP) loaded poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol) complex nanoparticles (CDDP-NPs) are confirmed to increase CD8 T cells within non-irradiated tumors and boost the abscopal effect of RT plus anti-PD1, and more strongly than CDDP. Compared to RT and RT + CDDP, RT + CDDP-NPs induced greater immunogenic cell death (ICD) with enhanced proportion of Calreticulin Lewis lung cancer (LLC) cells (16.47%, 20.53% and 27.03%), along with which more CD8 T cells were infiltrated into CDDP-NP treated irradiated tumors in the unilateral LLC tumor model. In the bilateral LLC tumor model, RT + CDDP-NPs significantly induced more chemokine (C-X-C motif) ligand 10 (CXCL10) secretion (36.3, 44.19 and 56.37 pg mL), which corresponded to greater CD8 T cell infiltration in the non-irradiated tumors (0.19%, 0.20% and 0.72%). Finally, compared to RT + anti-PD1 and RT + anti-PD1 + CDDP, RT + anti-PD1 + CDDP-NPs significantly inhibited the growth of non-irradiated tumors more forcefully, as indicated by the respective tumor volumes of 1141, 1146 and 585 mm. This is the first study to show that CDDP-NPs can amplify RT-induced immune activation and break through the efficiency limitation of the RT plus anti-PD1 induced abscopal effect.
放射治疗（RT）的远隔效应具有临床意义，但很少发生。尽管抗程序性细胞死亡蛋白1抗体（抗PD1）可能会增强接受RT治疗患者的远隔效应，但其发生率仍低于30%。一个主要限制是非照射肿瘤内CD8 T细胞数量稀少。在此，已证实负载顺铂（CDDP）的聚（L-谷氨酸）-接枝-甲氧基聚（乙二醇）复合纳米颗粒（CDDP-NPs）可增加非照射肿瘤内的CD8 T细胞数量，并增强RT联合抗PD1的远隔效应，且比CDDP的作用更强。与RT和RT + CDDP相比，RT + CDDP-NPs诱导了更强的免疫原性细胞死亡（ICD），钙网蛋白在Lewis肺癌（LLC）细胞中的比例增加（分别为16.47%、20.53%和27.03%），与此同时，在单侧LLC肿瘤模型中，更多的CD8 T细胞浸润到经CDDP-NP处理的照射肿瘤中。在双侧LLC肿瘤模型中，RT + CDDP-NPs显著诱导更多趋化因子（C-X-C基序）配体10（CXCL10）分泌（分别为36.3、44.19和56.37 pg/mL），这与非照射肿瘤中更多的CD8 T细胞浸润相对应（分别为0.19%、0.20%和0.72%）。最后，与RT +抗PD1和RT +抗PD1 + CDDP相比，RT +抗PD1 + CDDP-NPs更有力地显著抑制了非照射肿瘤的生长，各自的肿瘤体积分别为1141、1146和585 mm³表明了这一点。这是第一项表明CDDP-NPs可增强RT诱导的免疫激活并突破RT联合抗PD1诱导远隔效应效率限制的研究。
