Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Nat Commun. 2023 Apr 12;14(1):2087. doi: 10.1038/s41467-023-37825-x.
Combination of radiation therapy (RT) with immune checkpoint blockade can enhance systemic anti-tumor T cell responses. Here, using two mouse tumor models, we demonstrate that adding long-acting CD122-directed IL-2 complexes (IL-2c) to RT/anti-PD1 further increases tumor-specific CD8 T cell numbers. The highest increase (>50-fold) is found in the blood circulation. Compartmental analysis of exhausted T cell subsets shows that primarily undifferentiated, stem-like, tumor-specific CD8 T cells expand in the blood; these cells express the chemokine receptor CXCR3, which is required for migration into tumors. In tumor tissue, effector-like but not terminally differentiated exhausted CD8 T cells increase. Consistent with the surge in tumor-specific CD8 T cells in blood that are migration and proliferation competent, we observe a CD8-dependent and CXCR3-dependent enhancement of the abscopal effect against distant/non-irradiated tumors and find that CD8 T cells isolated from blood after RT/anti-PD1/IL-2c triple treatment can be a rich source of tumor-specific T cells for adoptive transfers.
放射治疗 (RT) 与免疫检查点阻断的联合应用可以增强全身抗肿瘤 T 细胞反应。在这里，我们使用两种小鼠肿瘤模型，证明在 RT/抗 PD1 的基础上添加长效 CD122 定向 IL-2 复合物 (IL-2c) 可进一步增加肿瘤特异性 CD8 T 细胞数量。在血液中发现的增加最高（>50 倍）。耗竭 T 细胞亚群的区室分析表明，主要是未分化的、干细胞样的、肿瘤特异性 CD8 T 细胞在血液中扩增；这些细胞表达趋化因子受体 CXCR3，这是迁移到肿瘤中所必需的。在肿瘤组织中，效应样但不是终末分化的耗竭 CD8 T 细胞增加。与血液中具有迁移和增殖能力的肿瘤特异性 CD8 T 细胞的激增一致，我们观察到对远处/未照射肿瘤的远隔效应的 CD8 依赖性和 CXCR3 依赖性增强，并且发现 RT/抗 PD1/IL-2c 三联治疗后从血液中分离的 CD8 T 细胞可以成为用于过继转移的丰富的肿瘤特异性 T 细胞来源。
