Markers of tumor-associated macrophages and microglia exhibit high intratumoral heterogeneity in human glioblastoma tissue.

IF 6.5 2区 医学 Q1 IMMUNOLOGY Oncoimmunology Pub Date : 2024-12-31 Epub Date: 2024-11-10 DOI:10.1080/2162402X.2024.2425124
Mikael Ispirjan, Sascha Marx, Eric Freund, Steffen K Fleck, Joerg Baldauf, Karl Roessler, Henry W S Schroeder, Sander Bekeschus
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Abstract

Background: Human glioblastoma multiforme (GBM) is a highly aggressive tumor with insufficient therapies available. Especially, novel concepts of immune therapies fail due to a complex immunosuppressive microenvironment, high mutational rates, and inter-patient variations. The intratumoral heterogeneity is currently not sufficiently investigated.

Methods: Biopsies from six different locations were taken in a cohort of 16 GBM patients who underwent surgery. The tissue slides were analyzed utilizing high-content imaging microscopy and algorithm-based image quantification. Several immune markers for macrophage and microglia subpopulations were investigated. Flow cytometry was used to validate key results. Besides the surface marker, cytokines were measured and categorized based on their heterogenicity and overall expression.

Results: M2-like antigens, including CD204, CD163, Arg1, and CSF1R, showed comparatively higher expression, with GFAP displaying the least intratumoral heterogeneity. In contrast, anti-tumor-macrophage-like antigens, such as PSGL-1, CD16, CD68, and MHC-II, exhibited low overall expression and concurrent high intratumoral heterogeneity. CD16 and PSGL-1 were the most heterogeneous antigens. High expression levels were observed for cytokines IL-6, VEGF, and CCL-2. VILIP-a was revealed to differentiate most in principle component analysis. Cytokines with the lowest overall expression, such as TGF-β1, β-NGF, TNF-α, and TREM1, showed low intratumoral heterogeneity, in contrast to βNGF, TNF-α, and IL-18, which displayed high heterogeneity despite low expression.

Conclusion: The study showed high intratumoral heterogeneity in GBM, emphasizing the need for a more detailed understanding of the tumor microenvironment. The described findings could be essential for future personalized treatment strategies and the implementation of reliable diagnostics in GBM.

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在人类胶质母细胞瘤组织中,肿瘤相关巨噬细胞和小胶质细胞的标记物表现出高度的瘤内异质性。
背景:人类多形性胶质母细胞瘤(GBM)是一种侵袭性极强的肿瘤,目前尚无足够的治疗方法。特别是,由于复杂的免疫抑制微环境、高突变率和患者之间的差异,新概念的免疫疗法失败了。瘤内异质性目前尚未得到充分研究:方法:在 16 名接受手术的 GBM 患者中,从 6 个不同部位提取活检组织。利用高内涵成像显微镜和基于算法的图像量化技术对组织切片进行分析。研究了巨噬细胞和小胶质细胞亚群的几种免疫标记物。流式细胞术用于验证主要结果。除了表面标记外,还对细胞因子进行了测量,并根据其异质性和总体表达进行了分类:结果:CD204、CD163、Arg1 和 CSF1R 等 M2 类抗原的表达量相对较高,而 GFAP 的瘤内异质性最小。相比之下,PSGL-1、CD16、CD68 和 MHC-II 等抗肿瘤巨噬细胞样抗原的总体表达量较低,同时瘤内异质性较高。CD16和PSGL-1是异质性最强的抗原。细胞因子 IL-6、VEGF 和 CCL-2 的表达水平较高。在原理成分分析中,VILIP-a的分化程度最高。总体表达量最低的细胞因子,如 TGF-β1、β-NGF、TNF-α 和 TREM1,显示出较低的瘤内异质性,相比之下,βNGF、TNF-α 和 IL-18 尽管表达量低,但却显示出较高的异质性:结论:该研究显示了 GBM 肿瘤内的高度异质性,强调了更详细了解肿瘤微环境的必要性。上述研究结果对于未来的个性化治疗策略和实施可靠的 GBM 诊断至关重要。
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来源期刊
Oncoimmunology
Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY
CiteScore
12.50
自引率
2.80%
发文量
276
审稿时长
24 weeks
期刊介绍: OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.
期刊最新文献
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