Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China.
Department of Oncology, Xuzhou Cancer Hospital, Xuzhou 221005, China.
Radiother Oncol. 2024 May;194:110213. doi: 10.1016/j.radonc.2024.110213. Epub 2024 Mar 7.
Poor penetration of transferred T cells represents a critical factor impeding the development of adoptive cell therapy in solid tumors. We demonstrated that iRGD-antiCD3 modification promoted both T cell infiltration and activation in our previous work. Interest in low-dose radiotherapy has recently been renewed due to its immuno-stimulatory effects including T cell recruitment. This study aims to explore the synergistic effects between low-dose radiotherapy and iRGD-antiCD3-modified T cells.
Flow cytometry was performed to assess the expression of iRGD receptors and chemokines. T cell infiltration was evaluated by immunohistofluorescence and in vivo real-time fluorescence imaging and antitumor effects were investigated by in vivo bioluminescence imaging in the gastric cancer peritoneal metastasis mouse model.
We found that 2 Gy irradiation upregulated the expression of all three iRGD receptors and T-cell chemokines. The addition of 2 Gy low-dose irradiation boosted the accumulation and penetration of iRGD-antiCD3-modified T cells in peritoneal tumor nodules. Combining 2 Gy low-dose irradiation with iRGD-antiCD3-modified T cells significantly inhibited tumor growth and prolonged survival in the peritoneal metastasis mouse model with a favorable safety profile.
Altogether, we demonstrated that low-dose radiotherapy could improve the antitumor potency of iRGD-antiCD3-modified T cells by promoting T cell infiltration, providing a rationale for exploring low-dose radiotherapy in combination of other adoptive T cell therapies in solid tumors.
转移 T 细胞的穿透能力差是阻碍实体瘤过继细胞治疗发展的一个关键因素。我们之前的研究表明，iRGD-抗 CD3 修饰可促进 T 细胞的浸润和激活。由于低剂量放疗具有免疫刺激作用，包括 T 细胞募集，因此最近人们对其重新产生了兴趣。本研究旨在探索低剂量放疗与 iRGD-抗 CD3 修饰的 T 细胞之间的协同作用。
采用流式细胞术评估 iRGD 受体和趋化因子的表达。通过免疫组化和体内实时荧光成像评估 T 细胞浸润，通过胃肿瘤腹膜转移小鼠模型中的体内生物发光成像研究抗肿瘤效果。
我们发现 2Gy 照射可上调所有三种 iRGD 受体和 T 细胞趋化因子的表达。添加 2Gy 低剂量照射可促进 iRGD-抗 CD3 修饰的 T 细胞在腹膜肿瘤结节中的聚集和穿透。将 2Gy 低剂量照射与 iRGD-抗 CD3 修饰的 T 细胞联合使用可显著抑制腹膜转移小鼠模型中的肿瘤生长并延长其生存时间，且具有良好的安全性。
综上所述，我们证明了低剂量放疗可通过促进 T 细胞浸润来提高 iRGD-抗 CD3 修饰的 T 细胞的抗肿瘤效力，为探索低剂量放疗与其他实体瘤过继性 T 细胞治疗联合应用提供了理论依据。
