LILRB2-containing small extracellular vesicles from glioblastoma promote tumor progression by promoting the formation and expansion of myeloid-derived suppressor cells,Cancer Immunology, Immunotherapy

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LILRB2-containing small extracellular vesicles from glioblastoma promote tumor progression by promoting the formation and expansion of myeloid-derived suppressor cells
Cancer Immunology, Immunotherapy ( IF 4.6 ) Pub Date : 2023-02-28 , DOI: 10.1007/s00262-023-03395-6
Peitao Wu ₁ , Yuhang Guo ₂ , Li Xiao ₁ , Jiaqi Yuan ₁ , Chao Tang ₃ , Jun Dong ₁ , Zhiyuan Qian ₁

Affiliation

Background

Leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2) was reported to be an inhibitory molecule with suppressive functions. sEVs mediate communication between cancer cells and other cells. However, the existence of LILRB2 on sEVs in circulation and the function of sEVs-LILRB2 are still unknown. This study aims to investigate the role of LILRB2 in GBM and determine how LILRB2 in sEVs regulates tumor immunity.

Methods

LILRB2 expression in normal brain and GBM tissues was detected by immunohistochemistry, and the effect of LILRB2 on prognosis was evaluated in an orthotopic brain tumor model. Next, a subcutaneous tumor model was constructed to evaluate the function of pirb in vivo. The immune cells in the tumor sites and spleen were detected by immunofluorescence staining and flow cytometry. Then, the presence of pirb in sEVs was confirmed by WB. The percentage of immune cells after incubation with sEVs from GL261 (GL261-sEVs) or sEVs from GL261-pirb⁺ (GL261-sEVs-pirb) was detected by flow cytometry. Then, the effect of pirb on sEVs was evaluated by a tumor-killing assay and proliferation assay. Finally, subcutaneous tumor models were constructed to evaluate the function of pirb on sEVs.

Results

LILRB2 was overexpressed in human GBM tissue and was closely related to an immunosuppressive TME in GBM. Then, a protumor ability of LILRB2 was observed in subcutaneous tumor models, which was related to lower CD8 + T cells and higher MDSCs (myeloid-derived suppressor cells) in the tumor and spleen compared to those of the control group. Next, we found that pirb on sEVs (sEVs-pirb) inhibits the function of CD8 + T cells by promoting the formation and expansion of MDSCs. Furthermore, the protumor function of sEVs-pirb was demonstrated in subcutaneous tumor models.

Conclusion

We discovered that LILRB2/pirb can be transmitted between GBM cells via sEVs and that pirb on sEVs induces the formation and expansion of MDSCs. The induced MDSCs facilitate the formation of an immunosuppressive TME.

Graphical Abstract

中文翻译：

来自胶质母细胞瘤的含 LILRB2 的小细胞外囊泡通过促进髓源性抑制细胞的形成和扩增来促进肿瘤进展

背景

据报道，白细胞免疫球蛋白样受体亚家族 B2 （LILRB2）是一种具有抑制功能的抑制分子。sEV 介导癌细胞与其他细胞之间的通讯。然而，流通中的 sEV 上是否存在 LILRB2 以及 sEVs-LILRB2 的功能仍然未知。本研究旨在探讨 LILRB2 在 GBM 中的作用，并确定 sEV 中的 LILRB2 如何调节肿瘤免疫。

方法

通过免疫组化检测正常脑和 GBM 组织中 LILRB2 的表达，并在原位脑肿瘤模型中评估 LILRB2 对预后的影响。接下来，构建皮下肿瘤模型以评估 pirb 在体内的功能。免疫荧光染色和流式细胞术检测肿瘤部位和脾脏中的免疫细胞。然后，WB 证实了 sEV 中存在 pirb。通过流式细胞术检测与 GL261 （GL261-sEVs）的 sEVs 或 GL261-pirb⁺ 的 sEVs （GL261-sEVs-pirb）孵育后免疫细胞的百分比。然后，通过肿瘤杀伤试验和增殖试验评价 pirb 对 sEVs 的影响。最后，构建皮下肿瘤模型以评估 pirb 对 sEVs 的功能。

结果

LILRB2 在人 GBM 组织中过表达，与 GBM 中的免疫抑制性 TME 密切相关。然后，在皮下肿瘤模型中观察到 LILRB2 的促肿瘤能力，这与与对照组相比，肿瘤和脾脏中 CD8 + T 细胞较低和骨髓衍生抑制细胞较高有关。接下来，我们发现 sEVs 上的 pirb （sEVs-pirb）通过促进 MDSC 的形成和扩增来抑制 CD8 + T 细胞的功能。此外，sEVs-pirb 的促肿瘤功能在皮下肿瘤模型中得到证实。