Lnc-H19-derived protein shapes the immunosuppressive microenvironment of glioblastoma.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-10-24 DOI:10.1016/j.xcrm.2024.101806

Junju Chen, Yixin Gao, Jian Zhong, Xujia Wu, Zhaojie Leng, Ming Liu, Yesheng Wang, Yuan Wang, Xuesong Yang, Nunu Huang, Feizhe Xiao, Maolei Zhang, Xuesong Liu, Nu Zhang

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引用次数: 0

Abstract

The immunosuppressive tumor microenvironment (TME) is a prominent feature of glioblastoma (GBM), the most lethal primary brain cancer resistant to current immunotherapies. The mechanisms underlying GBM-TME remain to be explored. We report that long non-coding RNA (LncRNA) H19 encodes an immune-related protein called H19-IRP. Functionally separated from H19 RNA, H19-IRP promotes GBM immunosuppression by binding to the CCL2 and Galectin-9 promoters and activating their transcription, thereby recruiting myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), leading to T cell exhaustion and an immunosuppressive GBM-TME. H19-IRP, overexpressed in clinical GBM samples, acts as a tumor-associated antigen (TAA) presented by major histocompatibility complex class I (MHC-I). A circular RNA vaccine targeting H19-IRP (circH19-vac) triggers a potent cytotoxic T cell response against GBM and inhibits GBM growth. Our results highlight the unrevealed function of H19-IRP in creating immunosuppressive GBM-TME by recruiting MDSCs and TAMs, supporting the idea of targeting H19-IRP with cancer vaccine for GBM treatment.

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Lnc-H19衍生蛋白塑造了胶质母细胞瘤的免疫抑制微环境。

免疫抑制性肿瘤微环境（TME）是胶质母细胞瘤（GBM）的一个突出特征，而胶质母细胞瘤是对当前免疫疗法具有抗药性的最致命的原发性脑癌。GBM-TME的内在机制仍有待探索。我们报告说，长非编码 RNA（LncRNA）H19 编码一种称为 H19-IRP 的免疫相关蛋白。H19-IRP 在功能上与 H19 RNA 分离，通过与 CCL2 和 Galectin-9 启动子结合并激活它们的转录，从而招募髓源性抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs），导致 T 细胞衰竭和免疫抑制性 GBM-TME，从而促进 GBM 免疫抑制。H19-IRP 在临床 GBM 样本中过表达，是一种由主要组织相容性复合体 I 类（MHC-I）呈现的肿瘤相关抗原（TAA）。以 H19-IRP 为靶点的环状 RNA 疫苗（circH19-vac）可引发针对 GBM 的强效细胞毒性 T 细胞反应，并抑制 GBM 的生长。我们的研究结果突显了H19-IRP在通过招募MDSCs和TAMs产生免疫抑制性GBM-TME方面尚未被揭示的功能，支持了用癌症疫苗靶向H19-IRP治疗GBM的想法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.