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基于异柠檬酸脱氢酶（IDH）状态剖析胶质瘤的免疫微环境：对免疫治疗的启示

Dissecting the Immunological Microenvironment of Glioma Based on IDH Status: Implications for Immunotherapy.

作者信息

Kikuchi Miyu, Takami Hirokazu, Kobayashi Yukari, Nagaoka Koji, Kitagawa Yosuke, Nomura Masashi, Takayanagi Shunsaku, Tanaka Shota, Saito Nobuhito, Kakimi Kazuhiro

机构信息

Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.

Department of Neurosurgery, Tokai University School of Medicine, Isehara 259-1193, Kanagawa, Japan.

出版信息

Cells. 2025 Jul 7;14(13):1035. doi: 10.3390/cells14131035.

DOI:10.3390/cells14131035
PMID:40643554
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12249363/
Abstract

Gliomas, particularly IDH-wildtype ones, are associated with poor prognosis, yet their immunological landscape remains uncertain. We analyzed RNA sequencing data from 55 glioma patients, estimating immune infiltration with CIBERSORTx and immune cell states via Ecotyper. IDH-wildtype gliomas showed significantly higher immune cell infiltration ( = 0.002), notably of regulatory T cells (Tregs) and macrophages, and a greater proportion of exhausted T cells compared to IDH-mutant gliomas. Clustering based on immune profiles revealed two groups. Cluster A, enriched for IDH-wildtype cases, exhibited heightened immune infiltration but also marked immunosuppression. Cluster B, which included both IDH-wildtype and mutant cases, showed lower levels of immune infiltration. Tumor-infiltrating lymphocyte (TIL) cultured from IDH-wildtype tumors demonstrated limited expansion following anti-PD-1, a CSF1R inhibitor, or a STAT3 inhibitor treatment, without clear cluster-specific differences. Tumor-reactive TILs were mainly observed in cluster A. These findings highlight that IDH-wildtype gliomas have an immunosuppressive and heterogeneous microenvironment, potentially limiting responses to single-agent immunotherapies. A personalized, multi-targeted approach addressing multiple immunosuppressive mechanisms may be essential to improve immunotherapy outcomes in this aggressive glioma subgroup.

摘要

胶质瘤，尤其是异柠檬酸脱氢酶（IDH）野生型胶质瘤，预后较差，但其免疫格局仍不明确。我们分析了55例胶质瘤患者的RNA测序数据，通过CIBERSORTx评估免疫浸润情况，并通过Ecotyper评估免疫细胞状态。与IDH突变型胶质瘤相比，IDH野生型胶质瘤的免疫细胞浸润显著更高（P = 0.002），尤其是调节性T细胞（Tregs）和巨噬细胞，且耗竭性T细胞的比例更高。基于免疫谱的聚类分析揭示了两组。富含IDH野生型病例的A组表现出增强的免疫浸润，但也有明显的免疫抑制。包括IDH野生型和突变型病例的B组免疫浸润水平较低。从IDH野生型肿瘤培养的肿瘤浸润淋巴细胞（TIL）在接受抗程序性死亡蛋白1（PD-1）、集落刺激因子1受体（CSF1R）抑制剂或信号转导和转录激活因子3（STAT3）抑制剂治疗后，增殖有限，且无明显的聚类特异性差异。肿瘤反应性TIL主要在A组中观察到。这些发现突出表明，IDH野生型胶质瘤具有免疫抑制和异质性的微环境，可能会限制对单药免疫疗法的反应。针对多种免疫抑制机制的个性化、多靶点方法可能对于改善这一侵袭性胶质瘤亚组的免疫治疗结果至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51d0/12249363/7681d0f661e7/cells-14-01035-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51d0/12249363/7681d0f661e7/cells-14-01035-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51d0/12249363/9cf63c91e63a/cells-14-01035-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51d0/12249363/92ee94a83564/cells-14-01035-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51d0/12249363/7681d0f661e7/cells-14-01035-g009.jpg

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