Chemoradiation Increases PD-L1 Expression in Certain Melanoma and Glioblastoma Cells.
Chemoradiation Increases PD-L1 Expression in Certain Melanoma and Glioblastoma Cells.
复制标题
DOI：
10.3389/fimmu.2016.00610
复制
发表时间：
2016
影响因子：
7.3
通讯作者：
Gaipl US
中科院分区：
文献类型：
--
作者：
Derer A;Spiljar M;Bäumler M;Hecht M;Fietkau R;Frey B;Gaipl US
免疫疗法目前正进入临床，以改善标准放化疗（RCT）的疗效。程序性细胞死亡受体配体1（PD - L1）是一个可能的靶点，阻断它可使依赖T细胞的抗肿瘤免疫反应得以执行。到目前为止，尚不清楚哪种RCT方案以及哪种分割方案会导致PD - L1表达增加，从而使阻断这种免疫抑制途径变得合理。因此，我们研究了放疗（RT）、化疗（CT）以及放化疗（RCT）对具有不同体细胞突变率的肿瘤实体的肿瘤细胞上PD - L1表面表达的影响。小鼠黑色素瘤（B16 - F10）、胶质母细胞瘤（GL261 - luc2）和结直肠癌（CT26）肿瘤细胞分别用达卡巴嗪、替莫唑胺以及伊立替康、奥沙利铂和氟尿嘧啶的组合进行治疗。此外，它们分别接受单剂量[10戈瑞（Gy）]或低分割（2×5 Gy）、常规分割（5×2 Gy）的放疗方案照射。通过流式细胞术测量PD - L1表面和细胞内干扰素（IFN）-γ的表达，并通过酶联免疫吸附测定（ELISA）测定白细胞介素 - 6（IL - 6）的释放。此外，通过膜联蛋白V - FITC/7 - AAD染色监测肿瘤细胞死亡。对于首次体内分析，选择了B16 - F10小鼠黑色素瘤模型。在B16 - F10和GL261 - luc2细胞中，特别是常规分割和低分割放疗导致表面PD - L1显著增加，而在CT26细胞中未观察到这种现象。此外，PD - L1在活肿瘤细胞上的表达更为明显，并且与肿瘤细胞中IFN - γ水平的升高相关。在黑色素瘤细胞中，CT是IL - 6释放的主要触发因素，而在胶质母细胞瘤细胞中则是常规分割放疗。在体内，只有分割放疗与达卡巴嗪联合才能诱导黑色素瘤细胞上的PD - L1表达。我们的结果表明，特别是放化疗后存在肿瘤细胞介导的PD - L1表达上调，这不仅取决于肿瘤实体的体细胞突变率。
Immunotherapy approaches currently make their way into the clinics to improve the outcome of standard radiochemotherapy (RCT). The programed cell death receptor ligand 1 (PD-L1) is one possible target that, upon blockade, allows T cell-dependent antitumor immune responses to be executed. To date, it is unclear which RCT protocol and which fractionation scheme leads to increased PD-L1 expression and thereby renders blockade of this immune suppressive pathway reasonable. We therefore investigated the impact of radiotherapy (RT), chemotherapy (CT), and RCT on PD-L1 surface expression on tumor cells of tumor entities with differing somatic mutation prevalence. Murine melanoma (B16-F10), glioblastoma (GL261-luc2), and colorectal (CT26) tumor cells were treated with dacarbazine, temozolomide, and a combination of irinotecan, oxaliplatin, and fluorouracil, respectively. Additionally, they were irradiated with a single dose [10 Gray (Gy)] or hypo-fractionated (2 × 5 Gy), respectively, norm-fractionated (5 × 2 Gy) radiation protocols were used. PD-L1 surface and intracellular interferon (IFN)-gamma expression was measured by flow cytometry, and IL-6 release was determined by ELISA. Furthermore, tumor cell death was monitored by AnnexinV-FITC/7-AAD staining. For first in vivo analyses, the B16-F10 mouse melanoma model was chosen. In B16-F10 and GL261-luc2 cells, particularly norm-fractionated and hypo-fractionated radiation led to a significant increase of surface PD-L1, which could not be observed in CT26 cells. Furthermore, PD-L1 expression is more pronounced on vital tumor cells and goes along with increased levels of IFN-gamma in the tumor cells. In melanoma cells CT was the main trigger for IL-6 release, while in glioblastoma cells it was norm-fractionated RT. In vivo, fractionated RT only in combination with dacarbazine induced PD-L1 expression on melanoma cells. Our results suggest a tumor cell-mediated upregulation of PD-L1 expression following in particular chemoradiation that is not only dependent on the somatic mutation prevalence of the tumor entity.
登录
查看更多内容
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
4.4
作者：
Iwai, Y;Terawaki, S;Honjo, T
通讯作者：
Honjo, T
影响因子：
3.1
作者：
Muth, Carolin;Ruebner, Yvonne;Gaipl, Udo S.
通讯作者：
Gaipl, Udo S.
影响因子：
3.9
作者：
Mangsbo, Sara M.;Sandin, Linda C.;Totterman, Thomas H.
通讯作者：
Totterman, Thomas H.