Tomita Mayu, Yasui Hironobu, Higashikawa Kei, Nakajima Kohei, Takakura Hideo, Shiga Tohru, Kuge Yuji, Ogawa Mikako
Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812, Japan.
Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan.
EJNMMI Res. 2018 Aug 16;8(1):82. doi: 10.1186/s13550-018-0433-1.
Programmed cell death 1 (PD-1) inhibitors act as immune checkpoint inhibitors and are more effective for improving survival time with less toxicity as compared with conventional chemotherapies. In anti PD-1 therapy, it is important to evaluate metabolism in the cancer microenvironment, as this helps to clarify the pathological conditions. Herein, we investigate the early effects of PD-1 therapy on 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) uptake in vivo, focusing on cell distribution and glycolysis in both cancer and immune cells.
In a B16F10 melanoma model, [F]FDG-positron emission tomography (PET) was performed before treatment and 7 days after the start of treatment. Values were calculated as the percentage-injected activity per gram of tissue (%IA/g). Flow-cytometry was then performed to assess immune cell populations and glucose metabolism. There was a negligible difference in [F]FDG uptake between tumors in the treatment group and non-treatment group before the treatment. In contrast, mean [F]FDG uptake in the treatment group tumors was significantly higher (8.06 ± 0.48 %IA/g; P = 0.0074) than that in the non-treatment group (4.02 ± 1.03 %IA/g) after anti PD-1 treatment. Assessment of tumor immune cell populations showed that treatment slightly enriched CD8 T cells and CD4 T cells; however, infiltration of immune cells was negligible, and thus, immune cells were not responsible for the increase in [F]FDG uptake. On the other hand, anti PD-1 treatment significantly increased glucose transporter 1 (GLUT1) and hexokinase II expression in CD45 cancer cells, indicating that anti PD-1 treatment increased glucose metabolism in cancer cells.
The present study shows that anti PD-1 therapy increases glucose metabolism in cancer cells.
程序性细胞死亡蛋白1（PD-1）抑制剂作为免疫检查点抑制剂，与传统化疗相比，在提高生存时间方面更有效，且毒性更小。在抗PD-1治疗中，评估癌症微环境中的代谢情况很重要，因为这有助于阐明病理状况。在此，我们研究了PD-1治疗对体内2-脱氧-2-[F]氟-D-葡萄糖（[F]FDG）摄取的早期影响，重点关注癌细胞和免疫细胞中的细胞分布及糖酵解。
在B16F10黑色素瘤模型中，于治疗前及治疗开始后7天进行[F]FDG正电子发射断层扫描（PET）。数值以每克组织注射活性百分比（%IA/g）计算。然后进行流式细胞术以评估免疫细胞群体和葡萄糖代谢。治疗前，治疗组和未治疗组肿瘤之间的[F]FDG摄取差异可忽略不计。相比之下，抗PD-1治疗后，治疗组肿瘤的平均[F]FDG摄取量（8.06±0.48 %IA/g；P = 0.0074）显著高于未治疗组（4.02±1.03 %IA/g）。对肿瘤免疫细胞群体的评估显示，治疗使CD8 T细胞和CD4 T细胞略有富集；然而，免疫细胞的浸润可忽略不计，因此，免疫细胞并非[F]FDG摄取增加的原因。另一方面，抗PD-1治疗显著增加了CD45癌细胞中葡萄糖转运蛋白1（GLUT1）和己糖激酶II的表达，表明抗PD-1治疗增加了癌细胞中的葡萄糖代谢。
本研究表明，抗PD-1治疗可增加癌细胞中的葡萄糖代谢。
