Hua Zhan, Wu Shan, Zhang Yulian, Wang Xiuhong, Cui Ju, Li Yunxuan, Yang Chengcheng, Zhai Min, Deng Bo, Yu Bin, Huang Jian-Dong, Wang Zai, Zhou Jianjun
Department of General Surgery, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
Research Center for Translational Medicine, Cancer Stem Cell Institute, East Hospital, Tongji University School of Medicine, Shanghai, China.
Front Med (Lausanne). 2023 Oct 31;10:1284120. doi: 10.3389/fmed.2023.1284120. eCollection 2023.
Liver metastasis is one of the primary causes of death for the patients with pancreatic neuroendocrine tumors (PNETs). However, no curative therapy has been developed so far.
The anti-tumor efficacy of a genetically engineered tumor-targeting YB1 was evaluated on a non-functional INR1G9 liver metastasis model. Differential inflammatory factors were screened by Cytometric Bead Array. Antibody depletion assay and liver-targeted AAV2/8 expression vector were used for functional evaluation of the differential inflammatory factors.
We demonstrated that YB1 showed significant anti-tumor efficacy as a monotherapy. Since YB1 cannot infect INR1G9 cells, its anti-tumor effect was possibly due to the modulation of the tumor immune microenvironment. Two inflammatory factors IFNγ and CCL2 were elevated in the liver after YB1 administration, but only IFNγ was found to be responsible for the anti-tumor effect. Liver-targeted expression of IFNγ caused the activation of macrophages and NK cells, and reproduced the therapeutic effect of YB1 on liver metastasis.
We demonstrated that YB1 may exhibit anti-tumor effect mainly based on IFNγ induction. Targeted IFNγ therapy can replace YB1 for treating liver metastasis of PNETs.
肝转移是胰腺神经内分泌肿瘤（PNETs）患者的主要死亡原因之一。然而，目前尚未开发出治愈性疗法。
在非功能性INR1G9肝转移模型上评估基因工程肿瘤靶向YB1的抗肿瘤疗效。通过细胞计数珠阵列筛选差异炎症因子。采用抗体清除试验和肝靶向AAV2/8表达载体对差异炎症因子进行功能评估。
我们证明YB1作为单一疗法显示出显著的抗肿瘤疗效。由于YB1不能感染INR1G9细胞，其抗肿瘤作用可能是由于对肿瘤免疫微环境的调节。给予YB1后，肝脏中两种炎症因子IFNγ和CCL2升高，但仅发现IFNγ负责抗肿瘤作用。肝脏靶向表达IFNγ导致巨噬细胞和NK细胞活化，并重现了YB1对肝转移的治疗效果。
我们证明YB1可能主要基于诱导IFNγ发挥抗肿瘤作用。靶向IFNγ治疗可替代YB1治疗PNETs的肝转移。
