髓系来源抑制细胞在大剂量照射的 TRAMP-C1 肿瘤中的作用：一个治疗靶点和评估肿瘤微环境的指标。
Role of Myeloid-Derived Suppressor Cells in High-Dose-Irradiated TRAMP-C1 Tumors: A Therapeutic Target and an Index for Assessing Tumor Microenvironment.
机构信息
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; Radiation Biology Research Center, Institute for Radiologic Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Radiation Biology Research Center, Institute for Radiologic Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Medical Imaging and Radiologic Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Radiation Oncology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan.
出版信息
Int J Radiat Oncol Biol Phys. 2021 Apr 1;109(5):1547-1558. doi: 10.1016/j.ijrobp.2020.11.004. Epub 2020 Nov 12.
PURPOSE
To investigate the temporal and spatial infiltration of TRAMP-C1 tumors by myeloid-derived suppressor cells (MDSCs) after high-dose radiation therapy (RT), and to explore their effect on tumor growth.
METHODS AND MATERIALS
TRAMP-C1 intramuscularly tumors were irradiated with a single dose of 8 Gy or 25 Gy. The dynamics of infiltrated MDSCs and their intratumoral spatial distribution were assessed by immunohistochemistry and flow cytometry. Cytokine levels in the blood and tumor were analyzed by multiplex immunoassay. Mice were injected with anti-Gr-1 antibody to determine whether MDSCs affect tumor growth after RT.
RESULTS
CD11bGr-1 MDSCs infiltrated TRAMP-C1 tumors irradiated with 25 Gy, but not 8 Gy, within 4 hours and recruitment persisted for at least 2 weeks. Both CD11bLy6GLy6C polymorphonuclear-MDSCs (PMN-MDSCs) and CD11bLy6GLy6C monocytic-MDSCs (M-MDSCs) were involved. Tumor RT also increased the representation of both MDSC subpopulations in the spleen and peripheral blood. Levels of multiple cytokines were increased in the tumors at 2 weeks, including GM-CSF, G-CSF, CCL-3, CCL-5, CXCL-5, IL-6, IL-17α, and VEGF-a; while G-CSF, IL-6, and TNF-α levels increased in the blood. PMN-MDSCs aggregated in the central necrotic region of the irradiated tumors over time, where they were associated with avascular hypoxia (CD31PIMO). MDSCs expressed the proangiogenic factor, matrix metalloproteinase-9, and, within the necrotic area, high levels of arginase-1 and indoleamine 2,3-dioxygenase. Depletion of PMN-MDSCs by Gr-1 antibody increased the efficacy of high-dose RT.
CONCLUSIONS
PMN-MDSCs infiltrate TRAMP-C1 tumors after high-dose RT. Their spatial distribution suggests they are involved in the evolution of an intratumoral state of necrosis associated with avascular hypoxia, and their phenotype is consistent with them being immunosuppressive. They appear to promote tumor growth after RT, making them a prime therapeutic target for therapeutic intervention. Assessment of MDSCs and cytokine levels in blood could be an index of the need for such an intervention.
目的
研究高剂量放射治疗（RT）后骨髓来源抑制细胞（MDSC）在 TRAMP-C1 肿瘤中的时空浸润，并探讨其对肿瘤生长的影响。
方法与材料
将 TRAMP-C1 肌肉内肿瘤用单剂量 8 Gy 或 25 Gy 照射。通过免疫组化和流式细胞术评估浸润性 MDSC 的动力学及其肿瘤内的空间分布。通过多重免疫测定分析血液和肿瘤中的细胞因子水平。用抗 Gr-1 抗体注射小鼠，以确定 MDSC 是否会影响 RT 后的肿瘤生长。
结果
在 4 小时内，25 Gy 照射的 TRAMP-C1 肿瘤中浸润了 CD11bGr-1 MDSC，但 8 Gy 照射则没有，并且募集持续至少 2 周。CD11bLy6GLy6C 多形核 MDSC（PMN-MDSC）和 CD11bLy6GLy6C 单核 MDSC（M-MDSC）均参与其中。肿瘤 RT 还增加了脾脏和外周血中这两种 MDSC 亚群的代表。在 2 周时，肿瘤中多种细胞因子的水平升高，包括 GM-CSF、G-CSF、CCL-3、CCL-5、CXCL-5、IL-6、IL-17α 和 VEGF-a；而血液中的 G-CSF、IL-6 和 TNF-α水平升高。PMN-MDSC 随时间在照射肿瘤的中央坏死区聚集，在那里它们与无血管缺氧（CD31PIMO）相关。MDSC 表达促血管生成因子基质金属蛋白酶-9，并且在坏死区，高水平的精氨酸酶-1 和吲哚胺 2,3-双加氧酶。用 Gr-1 抗体耗尽 PMN-MDSC 可增加高剂量 RT 的疗效。
结论
PMN-MDSC 在高剂量 RT 后浸润 TRAMP-C1 肿瘤。它们的空间分布表明它们参与了与无血管缺氧相关的肿瘤内坏死状态的演变，其表型与它们的免疫抑制作用一致。它们似乎在 RT 后促进肿瘤生长，使其成为治疗干预的主要治疗靶点。血液中 MDSC 和细胞因子水平的评估可能是需要进行这种干预的指标。
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