Zhang Ting, Adams Claire L, Fejer Gyorgy, Ercolano Emanuela, Cutajar Jonathan, Na Juri, Sahm Felix, Hanemann C Oliver
Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth, Devon, PL6 8BU, UK.
Institute of Cancer, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China.
J Exp Clin Cancer Res. 2025 May 27;44(1):162. doi: 10.1186/s13046-025-03419-2.
Meningiomas are the most common primary intracranial tumours, with clinical behaviours ranging from benign to highly aggressive forms. The World Health Organisation classifies meningiomas into various grades, guiding prognosis and treatment. While surgery is effective for low-grade meningiomas, certain grade 1 tumours, as well as grade 2, 3, and recurrent cases are more aggressive and require new therapeutic approaches. Immunotherapy shows promise, with early-stage clinical trials demonstrating encouraging results. The tumour microenvironment (TME), particularly tumour-associated macrophages (TAMs), plays a pivotal role in tumour progression. TAMs influence tumour growth, metastasis, and immune evasion. However, their role in meningiomas, especially in relation to genomic mutations, remains poorly understood. Understanding how genetic alterations affect the TME is critical for developing targeted immunotherapies.
This study employed multiplex immunohistochemistry and bulk RNA sequencing to explore immune infiltration in genetically stratified meningioma tissues and matched three-dimensional (3D) spheroid models. We compared immune cell populations across parental tissues, two-dimensional (2D) monolayer cultures, and 3D spheroid models. In addition, co-culture experiments were conducted, introducing M2-polarised macrophages derived from peripheral blood mononuclear cells to study the interactions between immune cells and tumour cells.
Our findings revealed significant differences in the immune infiltration patterns associated with specific genotypes and methylation classes, especially M2-like TAMs. Notably, the 3D spheroid models more closely replicated the TME observed in parental tissues compared to traditional 2D monolayer cultures, offering a superior platform for immune infiltration studies. Furthermore, co-culture experiments demonstrated that M2-polarised macrophages could effectively infiltrate tumour cells, promote tumour cell proliferation while inhibiting invasion, suggesting IL-6-mediated signalling in tumour progression.
These findings suggest that 3D co-culture models offer an excellent system for studying the role of immune cells, specifically TAMs, in meningioma progression. By providing a more accurate representation of the TME, these models can help identify novel immunotherapy strategies aimed at modulating the immune response within meningiomas. Ultimately, this approach may improve therapeutic outcomes and quality of life for patients with meningioma by enhancing the effectiveness of existing treatments or by offering new immunotherapeutic options.
脑膜瘤是最常见的原发性颅内肿瘤，其临床行为从良性到高度侵袭性不等。世界卫生组织将脑膜瘤分为不同级别，以指导预后和治疗。虽然手术对低级别脑膜瘤有效，但某些1级肿瘤以及2级、3级和复发性病例更具侵袭性，需要新的治疗方法。免疫疗法显示出前景，早期临床试验取得了令人鼓舞的结果。肿瘤微环境（TME），尤其是肿瘤相关巨噬细胞（TAM），在肿瘤进展中起关键作用。TAM影响肿瘤生长、转移和免疫逃逸。然而，它们在脑膜瘤中的作用，特别是与基因组突变的关系，仍知之甚少。了解基因改变如何影响TME对于开发靶向免疫疗法至关重要。
本研究采用多重免疫组织化学和批量RNA测序，以探索基因分层的脑膜瘤组织和匹配的三维（3D）球体模型中的免疫浸润情况。我们比较了亲代组织、二维（2D）单层培养物和3D球体模型中的免疫细胞群体。此外，进行了共培养实验，引入源自外周血单核细胞的M2极化巨噬细胞，以研究免疫细胞与肿瘤细胞之间的相互作用。
我们的研究结果显示，与特定基因型和甲基化类别相关的免疫浸润模式存在显著差异，尤其是M2样TAM。值得注意的是，与传统的2D单层培养相比，3D球体模型更紧密地复制了亲代组织中观察到的TME，为免疫浸润研究提供了一个优越的平台。此外，共培养实验表明，M2极化巨噬细胞可以有效浸润肿瘤细胞，促进肿瘤细胞增殖，同时抑制侵袭，提示IL-6介导的信号传导在肿瘤进展中的作用。
这些发现表明，3D共培养模型为研究免疫细胞，特别是TAM在脑膜瘤进展中的作用提供了一个优秀的系统。通过更准确地呈现TME，这些模型有助于识别旨在调节脑膜瘤内免疫反应的新型免疫治疗策略。最终，这种方法可能通过提高现有治疗的有效性或提供新的免疫治疗选择，改善脑膜瘤患者的治疗效果和生活质量。
