Tumor-Associated Macrophage-Derived Exosomal LINC01232 Induces the Immune Escape in Glioma by Decreasing Surface MHC-I Expression.
Tumor-Associated Macrophage-Derived Exosomal LINC01232 Induces the Immune Escape in Glioma by Decreasing Surface MHC-I Expression.
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DOI：
10.1002/advs.202207067
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发表时间：
2023-06
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影响因子：
--
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肿瘤相关巨噬细胞()的侵袭促进了胶质瘤的恶性转化，但其潜在机制尚不清楚。在此，有报道TAMs分泌胞外体LINC01232来诱导肿瘤免疫逃逸。从机制上讲，LINC01232直接与E2F2结合，促进E2F2进入细胞核；两者协同促进NBR1的转录。NBR1结合与泛素化的MHC-I蛋白通过泛素结构域结合增加，导致自噬溶酶体中MHC-I降解增加，肿瘤细胞表面MHC-I表达减少，进而导致肿瘤细胞逃避CD8+CTL免疫攻击。用shRNA阻断E2F2/NBR1/MHC-I信号通路或用相应抗体阻断E2F2/NBR1/MHC-I信号转导通路，可显著消除LINC01232的肿瘤支持作用，抑制M2型巨噬细胞驱动的肿瘤生长。重要的是，LINC01232基因的敲除增强了肿瘤细胞表面MHC-I的表达，并改善了与CD8+T细胞回输的反应。这项研究揭示了TAMs与胶质瘤之间存在关键的分子串扰，通过LINC01232/E2F2/NBR1/MHC-I轴支持恶性肿瘤的生长，提示靶向该轴可能具有治疗潜力。T2-TAMs分泌富含LINC01232的外切体进入肿瘤细胞，LINC01232直接与E2F2结合，促进E2F2进入细胞核；两者协同促进NBR1的转录水平。NBR1通过泛素结构域与泛素化的MHC-I蛋白结合增加，介导自噬溶酶体中MHC-I降解增加，肿瘤细胞表面MHC-I表达减少，进而导致肿瘤细胞逃避CD8+CTL免疫攻击。
Tumor‐associated macrophage (TAM) infiltration facilitates glioma malignancy, but the underlying mechanisms remain unclear. Herein, it is reported that TAMs secrete exosomal LINC01232 to induce tumor immune escape. Mechanistically, LINC01232 is found to directly bind E2F2 and promote E2F2 entry into the nucleus; the two synergistically promots the transcription of NBR1. The increase in binding between NBR1 binding and the ubiquitinating MHC‐I protein through the ubiquitin domain causes an increase in the degradation of MHC‐I in autophagolysosomes and a decrease in the expression of MHC‐I on the surface of tumor cells, which in turn led to tumor cell escape from CD8+ CTL immune attack. Disruption of E2F2/NBR1/MHC‐I signaling with shRNAs or blockade with the corresponding antibodies largely abolishes the tumor‐supportive effects of LINC01232 and inhibits tumor growth driven by M2‐type macrophages. Importantly, knockdown of LINC01232 enhances the expression of MHC‐I on the surface of tumor cells and improves the response to reinfusion with CD8+ T cells. This study reveals the existence of critical molecular crosstalk between TAMs and glioma mediates through the LINC01232/E2F2/NBR1/MHC‐I axis to support malignant tumor growth, indicating that targeting this axis may have therapeutic potential. T2‐TAMs secrete exosomes rich in LINC01232 into tumor cells, and LINC01232 directly binds E2F2 and promotes E2F2 entry into the nucleus; the two synergistically promote the transcription level of NBR1. The increased binding of NBR1 to the ubiquitinated MHC‐I protein through the ubiquitin domain mediates the increased degradation of MHC‐I in autophagolysosomes, and the decreased expression of MHC‐I on the surface of tumor cells, which in turn leads to tumor cells escape from CD8+ CTL immune attack.
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影响因子：
8.8
作者：
Kratochvill F;Neale G;Haverkamp JM;Van de Velde LA;Smith AM;Kawauchi D;McEvoy J;Roussel MF;Dyer MA;Qualls JE;Murray PJ
通讯作者：
Murray PJ
影响因子：
28.1
作者：
Kulkarni, Ashish;Chandrasekar, Vineethkrishna;Sengupta, Shiladitya
通讯作者：
Sengupta, Shiladitya
影响因子：
23.9
作者：
Lathia, Justin D.;Heddleston, John M.;Venere, Monica;Rich, Jeremy N.
通讯作者：
Rich, Jeremy N.
DOI：
10.1073/pnas.1113744109
发表时间：
2012-02-14
影响因子：
11.1
作者：
Cortez-Retamozo, Virna;Etzrodt, Martin;Pittet, Mikael J.
通讯作者：
Pittet, Mikael J.
肿瘤相关巨噬细胞的细胞和分子起源。
DOI：
10.1126/science.1252510
发表时间：
2014-05-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franklin RA;Liao W;Sarkar A;Kim MV;Bivona MR;Liu K;Pamer EG;Li MO
通讯作者：
Li MO