Department of Tumor Biology and Cancer Research Institute, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Radiother Oncol. 2024 Nov;200:110480. doi: 10.1016/j.radonc.2024.110480. Epub 2024 Aug 17.
Local radiotherapy (RT) exerts immunostimulatory effects by inducing immunogenic cell death. However, it remains unknown whether in vitro-irradiated tumor cells can elicit anti-tumor responses and enhance the efficacy of local RT and immune checkpoint inhibitors when injected in vivo.
We tested the "in vitro-irradiated cancer vaccine (ICV)", wherein tumor cells killed by varying doses of irradiation and their supernatants are intravenously injected. We examined the efficacy of combining local RT (24 Gy in three fractions), PD-L1 blockade, and the ICV in a murine breast cancer model. The immune cell profiles were analyzed via flow cytometry and immunohistochemistry. The cytokine levels were measured by multiplex immunoassays.
The ICV significantly increased the effector memory phenotype and interferon-γ production capacity in splenic CD8 T cells. The in vitro-irradiated products contained immune response-related molecules. When combined with local RT and PD-L1 blockade, the ICV significantly delayed the growth of irradiated and non-irradiated tumors. The triple combination therapy increased the proportions of CD8 T cells and effector memory CD8 T cells while decreasing the proportion of CTLA-4 exhausted CD8 T cells within tumor microenvironment. Additionally, plasma level of interferon-γ and proliferation of effector T cells in the spleen and tumor-draining lymph nodes were significantly increased by the triple combination therapy.
The ICV enhanced the therapeutic efficacy of local RT and PD-L1 blockade by augmenting anti-tumor immune responses. Our findings suggest a therapeutic potential of in vitro-irradiation products of tumor cells.
局部放疗（RT）通过诱导免疫原性细胞死亡发挥免疫刺激作用。然而，目前尚不清楚体外照射的肿瘤细胞是否能够引发抗肿瘤反应，并增强局部 RT 和免疫检查点抑制剂的疗效，当它们在体内注射时。
我们测试了“体外照射的癌症疫苗（ICV）”，其中通过不同剂量的照射杀死肿瘤细胞及其上清液，并通过静脉注射。我们在小鼠乳腺癌模型中检验了局部 RT（24 Gy 分 3 次）、PD-L1 阻断和 ICV 联合使用的疗效。通过流式细胞术和免疫组织化学分析免疫细胞谱。通过多重免疫测定法测量细胞因子水平。
ICV 显著增加了脾 CD8 T 细胞中的效应记忆表型和干扰素-γ产生能力。体外照射产物含有免疫反应相关分子。当与局部 RT 和 PD-L1 阻断联合使用时，ICV 显著延缓了照射和未照射肿瘤的生长。三重联合治疗增加了肿瘤微环境中 CD8 T 细胞和效应记忆 CD8 T 细胞的比例，同时减少了 CTLA-4 耗尽的 CD8 T 细胞的比例。此外，三重联合治疗显著增加了血浆中干扰素-γ的水平和脾及肿瘤引流淋巴结中效应 T 细胞的增殖。
ICV 通过增强抗肿瘤免疫反应增强了局部 RT 和 PD-L1 阻断的治疗效果。我们的研究结果表明，肿瘤细胞体外照射产物具有治疗潜力。
