PD1 blockade alters cell-cycle distribution and affects 3′-deoxy-3′-[18F]fluorothymidine uptake in a mouse CT26 tumor model
PD1 blockade alters cell-cycle distribution and affects 3′-deoxy-3′-[18F]fluorothymidine uptake in a mouse CT26 tumor model
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PD1阻断改变细胞周期分布并影响小鼠CT26肿瘤模型中3-脱氧-3-[18F]氟胸苷的摄取
DOI：
10.1007/s12149-022-01782-0
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发表时间：
2022
影响因子：
2.6
通讯作者：
Ogawa Mikako
中科院分区：
文献类型：
--
作者：
Suzuki Motofumi;Matsuda Takuma;Nakajima Kohei;Yokouchi Yuta;Kuge Yuji;Ogawa Mikako
目的我们之前报道，程序性死亡受体-1 (PD1) 阻断改变肿瘤微环境 (TME)，影响肿瘤葡萄糖代谢和肿瘤 2-脱氧-2-[18F]氟-D-葡萄糖 ([18F]FDG) 摄取。在癌细胞中，高糖酵解使细胞能够维持快速增殖，因为糖酵解与癌细胞的增殖密切相关。因此，细胞增殖成像可以提供 TME 改变的更多细节。在本研究中，我们研究了 PD1 阻断导致的 TME 改变如何影响 3′-脱氧-3′-[18F]氟胸苷 ([18F]FLT) 的摄取，这是一种 18F 放射性标记的胸苷衍生物，被增殖细胞摄取。方法接种小鼠结肠癌 CT26 细胞的小鼠在第 0 天腹膜内注射抗 PD1 抗体，此时肿瘤体积超过50 mm3，第5天。在治疗前（第0天）和治疗后（第7天）进行[18F]FLT-PET成像。通过流式细胞术鉴定肿瘤浸润淋巴细胞（TIL）。通过放射自显影和免疫组织化学评估[18F]FLT在肿瘤组织中的积累和定位。通过流式细胞术分析暴露于细胞因子（白介素-2、干扰素[INF]-γ和肿瘤坏死因子[TNF]-α）的肿瘤和CT26细胞的细胞周期分布。结果PD1阻断使肿瘤组织中CD8+和CD4+T细胞增加，并显着抑制肿瘤增殖；然而，肿瘤[18F]FLT摄取保持不变。放射自显影和免疫组织化学显示，[18F]FLT 主要被癌细胞摄取，但 TIL 不摄取。流式细胞术分析表明，PD1阻断后G2/M期细胞数量增加。此外，INF-γ和TNF-α在体外显着增加G2/M期细胞。结论PD1阻断诱导的TME改变增加了G2/M期CT26肿瘤细胞，其具有高胸苷激酶1活性。因此，即使肿瘤增殖受到抑制，[18F]FLT也会被肿瘤细胞摄取。这一观察结果可能有助于评估免疫治疗的反应。
ObjectiveWe previously reported that alterations of the tumor microenvironment (TME) by programmed death receptor-1 (PD1) blockade affected tumor glucose metabolism and tumor 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake. In cancer cells, high glycolysis allows cells to sustain rapid proliferation since glycolysis is closely related to the proliferation of cancer cells. Therefore, imaging of cellular proliferation may provide more detail of TME alterations. In this study, we investigated how TME alterations by PD1 blockade affects the uptake of 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), which is a18F-radiolabeled thymidine derivative and is taken up by proliferating cells.MethodsMice inoculated with murine colon carcinoma CT26 cells were intraperitoneally administered an anti-PD1 antibody on Day 0, when the tumor volume exceeded 50 mm3, and Day 5. [18F]FLT-PET imaging was performed pre-treatment (Day 0) and post treatment (Day 7). Tumor infiltrating lymphocytes (TILs) were identified by flow cytometry. [18F]FLT accumulation and localization in tumor tissue was evaluated by autoradiography and immunohistochemistry. The cell-cycle distribution of tumors and CT26 cells exposed to cytokines (interleukin-2, interferon [INF]-γ, and tumor necrosis factor [TNF]-α) was analyzed by flow cytometry.ResultsPD1 blockade increased CD8+and CD4+T cells in tumor tissue and significantly suppressed tumor proliferation; however, tumor [18F]FLT uptake remained unchanged. Autoradiography and immunohistochemistry showed that [18F]FLT was mainly taken up by cancer cells, but not TILs. Flow cytometric analysis demonstrated that the population of cells in G2/M phase increased after PD1 blockade. Moreover, INF-γ and TNF-α significantly increased cells in G2/M phase in vitro.ConclusionPD1 blockade-induced alteration of the TME increased CT26 tumor cells in the G2/M phase, which have high thymidine kinase 1 activity. Therefore, [18F]FLT is taken up by tumor cells even if tumor proliferation is suppressed. This observation may be useful for evaluating the response to immunotherapy.
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DOI：
10.1016/s0021-9258(18)68484-4
发表时间：
1988-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J L Sherley;T J Kelly
通讯作者：
J L Sherley;T J Kelly
使用(5-O-二甲氧基三苯甲基-2-脱氧-3-O-nosyl-β-D-苏型呋喃戊糖基)胸腺嘧啶及其3-高放射化学产率合成3-脱氧-3-[18F]氟胸苷
影响因子：
3.1
作者：
Mikyung Yun;S. Oh;H. Ha;J. Ryu;D. Moon
通讯作者：
D. Moon
TNF-α 损害癌前皮肤细胞中的 S-G2/M 细胞周期检查点和环丁烷嘧啶二聚体修复：PI3K-Akt 通路的作用。
影响因子：
6.5
作者：
A. Faurschou;R. Gniadecki;D. Calay;H. Wulf
通讯作者：
H. Wulf
影响因子：
4
作者：
Lipson EJ;Forde PM;Hammers HJ;Emens LA;Taube JM;Topalian SL
通讯作者：
Topalian SL