BACKGROUND The lack of immune synergy with conventional chemoradiation could explain the failure of checkpoint inhibitors in current clinical trials for high-grade gliomas (HGGs). OBJECTIVE To analyze the impact of radiotherapy (RT), Temozolomide (TMZ) and antiprogrammed cell death protein 1 (αPD1) (as single or combined treatments) on the immune microenvironment of experimental HGGs. METHODS Mice harboring neurosphere /CT-2A HGGs received RT (4 Gy, single dose), TMZ (50 mg/kg, 4 doses) and αPD1 (100 μg, 3 doses) as monotherapies or combinations. The influence on survival, tumor volume, and tumor-infiltrating immune cells was analyzed. RESULTS RT increased total T cells (P = .0159) and cluster of differentiation (CD)8+ T cells (P = .0078) compared to TMZ. Lymphocyte subpopulations resulting from TMZ or αPD1 treatment were comparable with those of controls. RT reduced M2 tumor-associated macrophages/microglia (P = .0019) and monocytic myeloid derived suppressor cells (mMDSCs, P = .0003) compared to controls. The effect on mMDSC was also seen following TMZ and αPD1 treatment, although less pronounced (P = .0439 and P = .0538, respectively). Combining RT with TMZ reduced CD8+ T cells (P = .0145) compared to RT alone. Adding αPD1 partially mitigated this effect as shown by the increased CD8+ T cells/Tregs ratio, even if this result failed to reach statistical significance (P = .0973). Changing the combination sequence of RT, TMZ, and αPD1 did not alter survival nor the immune effects. CONCLUSION RT, TMZ, and αPD1 modify the immune microenvironment of HGG. The combination of RT with TMZ induces a strong immune suppression which cannot be effectively counteracted by αPD1.

中文翻译：

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放疗、替莫唑胺和抗程序性细胞死亡蛋白 1 治疗调节实验性高级别胶质瘤的免疫微环境

背景技术与常规放化疗缺乏免疫协同作用可以解释检查点抑制剂在目前针对高级别胶质瘤 (HGG) 的临床试验中失败的原因。目的 分析放疗 (RT)、替莫唑胺 (TMZ) 和抗程序性细胞死亡蛋白 1 (αPD1)（作为单一或联合治疗）对实验性 HGGs 免疫微环境的影响。方法 携带神经球/CT-2A HGG 的小鼠接受 RT（4 Gy，单剂量）、TMZ（50 mg/kg，4 剂量）和 αPD1（100 μg，3 剂量）作为单一疗法或组合。分析了对存活、肿瘤体积和肿瘤浸润免疫细胞的影响。结果 与 TMZ 相比，RT 增加了总 T 细胞 (P = .0159) 和分化簇 (CD)8+ T 细胞 (P = .0078)。由 TMZ 或 αPD1 治疗产生的淋巴细胞亚群与对照组相当。与对照组相比，RT 减少了 M2 肿瘤相关巨噬细胞/小胶质细胞 (P = .0019) 和单核细胞骨髓源性抑制细胞 (mMDSCs，P = .0003)。在 TMZ 和 αPD1 处理后也观察到对 mMDSC 的影响，尽管不太明显（分别为 P = .0439 和 P = .0538）。与单独的 RT 相比，RT 与 TMZ 相结合减少了 CD8+ T 细胞（P = .0145）。添加 αPD1 部分减轻了这种影响，如 CD8+ T 细胞/Tregs 比率增加所示，即使该结果未能达到统计显着性 (P = .0973)。改变 RT、TMZ 和 αPD1 的组合顺序并没有改变存活率和免疫效应。结论 RT、TMZ 和 αPD1 改变了 HGG 的免疫微环境。