Exosomal B7-H4 from irradiated glioblastoma cells contributes to increase FoxP3 expression of differentiating Th1 cells and promotes tumor growth.
Exosomal B7-H4 from irradiated glioblastoma cells contributes to increase FoxP3 expression of differentiating Th1 cells and promotes tumor growth.
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来自受辐射胶质母细胞瘤细胞的外泌体 B7-H4 有助于增加分化 Th1 细胞的 FoxP3 表达并促进肿瘤生长
DOI：
10.1016/j.redox.2022.102454
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发表时间：
2022-10
期刊：
影响因子：
11.4
通讯作者：
Yuan, Yawei
中科院分区：
文献类型：
--
作者：
Tian, Yunhong;Liu, Chunshan;Li, Zhiyong;Ai, Meiling;Wang, Baiyao;Du, Kunpeng;Liu, Wei;Wang, Hongmei;Yu, Peng;Chen, Chengcong;Lin, Jie;Xu, Anan;Li, Rong;Zhang, Weijun;Yuan, Yawei
胶质母细胞瘤（GBM）是最常见和最具侵袭性的原发性脑肿瘤。尽管已经开发了许多术后治疗策略，包括放射治疗，但肿瘤在治疗数年后不可避免地复发。共抑制分子B7-H4负调节T细胞免疫应答并促进免疫逃逸。外泌体介导细胞间通讯并启动肿瘤微环境（TME）中的免疫逃避。这项研究旨在确定B7-H4是否被辐射上调并加载到外泌体中，从而有助于免疫抑制和促进肿瘤生长。碘克沙醇密度梯度离心和流式细胞术用于验证外泌体B7-H4。幼稚T细胞分化为Th 1细胞，有或没有外来体。检测T细胞分泌的细胞因子和T细胞亚群标志物。在机制上，使用数据库和组织样品分析B7-H4和阿利克斯在GBM中的作用。使用免疫共沉淀和下拉测定来测试ATM与阿利克斯或STAT 3之间的直接相互作用。体外ATM激酶试验、蛋白质印迹和定点突变被用于评估ATM介导的STAT 3磷酸化。最后，在体内研究了外泌体B7-H4对免疫抑制和肿瘤生长的贡献。照射后GBM细胞的外泌体通过B7-H4在体内外降低T细胞的抗肿瘤免疫应答。从机制上讲，辐射通过增加ATM-ALIX相互作用来促进外泌体生物发生。此外，ATM-磷酸化的STAT 3被发现直接结合到B7-H4启动子以增加其表达。最后，辐射诱导的外泌体B7-H4的增加通过活化的STAT 1途径诱导了Th 1细胞分化期间FoxP 3的表达。在体内，外泌体B7-H4降低了GBM细胞的辐射敏感性，降低了GBM小鼠模型的存活率。这项研究表明，辐射增强的外泌体B7-H4促进了免疫抑制和肿瘤生长，因此确定了辐射和抗肿瘤免疫反应之间的直接联系。我们的研究结果表明，放疗与抗B7-H4治疗的联合施用可以改善局部肿瘤控制，并将外泌体B7-H4鉴定为潜在的肿瘤生物标志物。
Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor. Although numerous postoperative therapeutic strategies have already been developed, including radiotherapy, tumors inevitably recur after several years of treatment. The coinhibitory molecule B7–H4 negatively regulates T cell immune responses and promotes immune escape. Exosomes mediate intercellular communication and initiate immune evasion in the tumor microenvironment (TME). This study aimed to determine whether B7–H4 is upregulated by radiation and loaded into exosomes, thus contributing to immunosuppression and enhancing tumor growth. Iodixanol density-gradient centrifugation and flow cytometry were used to verify exosomal B7–H4. Naïve T cells were differentiated into Th1 cells, with or without exosomes. T cell-secreted cytokines and markers of T cell subsets were measured. Mechanistically, the roles of B7–H4, and ALIX in GBM were analyzed using databases and tissue samples. Co‐immunoprecipitation, and pull-down assays were used to tested the direct interactions between ATM and ALIX or STAT3. In vitro ATM kinase assays, western blotting, and site-directed mutation were used to assess ATM-mediated STAT3 phosphorylation. Finally, the contribution of exosomal B7–H4 to immunosuppression and tumor growth was investigated in vivo. Exosomes from irradiated GBM cells decreased the anti-tumor immune response of T cell in vitro and in vivo via delivered B7–H4. Mechanistically, irradiation promoted exosome biogenesis by increasing the ATM-ALIX interaction. Furthermore, the ATM-phosphorylated STAT3 was found to directly binds to the B7–H4 promoter to increase its expression. Finally, the radiation-induced increase in exosomal B7–H4 induced FoxP3 expression during Th1 cell differentiation via the activated STAT1 pathway. In vivo, exosomal B7–H4 decreased the radiation sensitivity of GBM cells, and reduced the survival of GBM mice model. This study showed that radiation-enhanced exosomal B7–H4 promoted immunosuppression and tumor growth, hence defining a direct link between irradiation and anti-tumor immune responses. Our results suggest that co-administration of radiotherapy with anti-B7-H4 therapy could improve local tumor control and identify exosomal B7–H4 as a potential tumor biomarker.
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影响因子：
8.7
作者：
Podojil JR;Miller SD
通讯作者：
Miller SD
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
头颈癌患者血浆中 PD-L1(+) 外泌体的临床意义。
DOI：
10.1158/1078-0432.ccr-17-2664
发表时间：
2018-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Theodoraki MN;Yerneni SS;Hoffmann TK;Gooding WE;Whiteside TL
通讯作者：
Whiteside TL
影响因子：
16.6
作者：
Sato H;Niimi A;Yasuhara T;Permata TBM;Hagiwara Y;Isono M;Nuryadi E;Sekine R;Oike T;Kakoti S;Yoshimoto Y;Held KD;Suzuki Y;Kono K;Miyagawa K;Nakano T;Shibata A
通讯作者：
Shibata A
影响因子：
4.3
作者：
Choi, Byung-Kwon;Fujiwara, Kenichiro;Donehower, Lawrence A.
通讯作者：
Donehower, Lawrence A.