脑胶质母细胞瘤来源的含 LILRB2 的小细胞外囊泡通过促进髓系来源抑制细胞的形成和扩增促进肿瘤进展。
LILRB2-containing small extracellular vesicles from glioblastoma promote tumor progression by promoting the formation and expansion of myeloid-derived suppressor cells.
机构信息
Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow, 215000, People's Republic of China.
Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou, China.
出版信息
Cancer Immunol Immunother. 2023 Jul;72(7):2179-2193. doi: 10.1007/s00262-023-03395-6. Epub 2023 Feb 28.
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.
背景
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性分子。外泌体介导癌细胞与其他细胞之间的通讯。然而，循环中外泌体中的 LILRB2 的存在及其外泌体 LILRB2 的功能尚不清楚。本研究旨在探讨 LILRB2 在 GBM 中的作用，并确定外泌体 LILRB2 如何调节肿瘤免疫。
方法
采用免疫组织化学法检测正常脑组织和 GBM 组织中 LILRB2 的表达，在原位脑肿瘤模型中评估 LILRB2 对预后的影响。然后，构建皮下肿瘤模型，体内评估 pirb 的功能。通过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，通过 WB 证实 pirb 在外泌体中存在。通过流式细胞术检测与 GL261 来源的外泌体（GL261-sEVs）或 GL261-pirb 来源的外泌体（GL261-sEVs-pirb）孵育后免疫细胞的百分比。然后，通过杀伤试验和增殖试验评估 pirb 对 sEVs 的影响。最后，构建皮下肿瘤模型，评估 pirb 对 sEVs 的功能。
结果
LILRB2 在人 GBM 组织中过度表达，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，与对照组相比，肿瘤和脾脏中的 CD8+T 细胞较低，MDSCs（髓源性抑制细胞）较高。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，在皮下肿瘤模型中证实了 sEVs-pirb 的促肿瘤功能。
结论
我们发现 LILRB2/pirb 可以通过外泌体在 GBM 细胞之间传递，外泌体上的 pirb 诱导 MDSC 的形成和扩增。诱导的 MDSC 促进了免疫抑制性 TME 的形成。
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