Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun 130021, P.R. China.
Department of Ophthalmology, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China.
J Radiat Res. 2020 Nov 16;61(6):851-859. doi: 10.1093/jrr/rraa077.
Radiation therapy is an important method in tumor treatment with distinct responses. This study aimed to investigate the immune effects of radiation therapy on the syngeneic gastric tumor model. Mouse forestomach carcinoma (MFC) cells were irradiated with different X-ray doses. Cell proliferation was determined by clonogenic assay. Gene and protein expression were determined by real-time quantitative PCR and western blot, respectively. The tumor model was established by subcutaneously injecting tumor cells in 615-(H-2 K) mice. Levels of immune-related factors in tumor tissues were determined by immunohistochemistry and flow cytometry. 5 Gy × 3 (three subfractions with 4 h interval) treatment significantly inhibited cell proliferation. Protein expression of stimulator of interferon genes (Sting) and gene expression of IFNB1, TNFα as well as CXCL-9 significantly increased in MFC cells after irradiation. In the MFC mouse model, no obvious tumor regression was observed after irradiation treatment. Further studies showed Sting protein expression, infiltration of dendritic cells and T cells, and significantly increased PD-1/PD-L1 expression in tumor tissues. Moreover, the irradiation treatment activated T cells and enhanced the therapeutic effects of anti-PD1 antibody against MFC tumor. Our data demonstrated that although the MFC tumor was not sensitive to radiation therapy, the tumor microenvironment could be primed after irradiation. Radiation therapy combined with immunotherapy can greatly improve anti-tumor activities in radiation therapy-insensitive tumor models.
放射治疗是肿瘤治疗的一种重要方法，具有明显的疗效。本研究旨在探讨放射治疗对同源胃肿瘤模型的免疫效应。用不同剂量 X 射线照射小鼠前胃癌细胞（MFC）。用集落形成实验测定细胞增殖。实时定量 PCR 和 Western blot 分别测定基因和蛋白表达。通过将肿瘤细胞皮下注射到 615-（H-2 K）小鼠中建立肿瘤模型。用免疫组化和流式细胞术测定肿瘤组织中免疫相关因子的水平。5 Gy×3（3 次分割，间隔 4 h）治疗明显抑制细胞增殖。照射后 MFC 细胞中干扰素基因刺激物（Sting）蛋白表达和 IFNB1、TNFα 以及 CXCL-9 基因表达显著增加。在 MFC 小鼠模型中，照射治疗后未见明显肿瘤消退。进一步的研究表明，Sting 蛋白表达、树突状细胞和 T 细胞浸润以及肿瘤组织中 PD-1/PD-L1 表达显著增加。此外，照射治疗激活了 T 细胞，并增强了抗 PD-1 抗体对 MFC 肿瘤的治疗效果。我们的数据表明，尽管 MFC 肿瘤对放射治疗不敏感，但照射后肿瘤微环境可以被激活。放射治疗联合免疫治疗可以大大提高放射治疗不敏感肿瘤模型的抗肿瘤活性。
