Background: GlioblastomaIDH-wildtype (GBMIDH-wt) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping its tumor microenvironment (TME) regulate tumor progression and treatment response. The aim of this study was to characterize the main immunosuppressive elements of the GBMIDH-wt TME.Methods:Immunohistochemistry for CD3, CD4, CD8, CD163, programmed death ligand 1 (PD-L1) and programmed death 1 (PD1) was performed on surgical tumor specimens from patients diagnosed with GBMIDH-wt, according to the CNS WHO 2021 criteria. The impact of categorical variables on time-dependent outcomes such as overall survival (OS) and progression-free survival (PFS) has been estimated through the Kaplan–Meier method.Results:We included 30 patients (19 males and 11 females), median age of 59.8 years (range 40.2–69.1 years). All patients underwent surgery followed by temozolomide concurrent with and adjuvant to radiotherapy. MGMT was methylated in 14 patients (47%) and unmethylated in 16 patients (53%). The overall absolute percentages of CD4+ lymphocytes, both intratumoral and perivascular, were significantly more represented than CD8+ lymphocytes in the TME (p= 0.02). A low density of CD4+ lymphocytes (≤10%) was found to be a favorable prognostic factor for GBM outcome (p= 0.02). Patients with MGMT methylated and unmethylated tumors exhibited a distinct TME composition, with a significant higher number of perivascular CD8+ lymphocytes (p= 0.002), intratumoral CD8+ lymphocytes (p= 0.0024) and perivascular CD4+ lymphocytes (p= 0.014) in MGMT unmethylated tumors. PD-L1 expression in tumor cell surface was observed in four tumors (13.3%), and PD1 expression in infiltrating T lymphocytes was observed in nine (30%) tumors, with predominantly perivascular distribution.Conclusions:MGMT methylated and unmethylated tumors exhibit different immune profiles, likely reflecting the different biology of these tumors. The expression of PD-L1 in GBMIDH-wt patients is confined to a small subpopulation. While we found a significant association between low CD4+ lymphocyte density (≤10%) and survival, given the small numbers of our cohort, the prognostic value of CD4+ lymphocyte density will need to be validated in large-scale studies.
背景：IDH野生型胶质母细胞瘤（GBMIDH-wt）是成人中最具侵袭性的脑肿瘤，其特征是免疫抑制微环境。塑造其肿瘤微环境（TME）的不同因素调控着肿瘤进展和治疗反应。本研究旨在描述GBMIDH-wt TME中主要免疫抑制成分的特征。 方法：根据2021年中枢神经系统世界卫生组织分类标准，对诊断为GBMIDH-wt的患者手术肿瘤标本进行CD3、CD4、CD8、CD163、程序性死亡配体1（PD-L1）和程序性死亡受体1（PD1）的免疫组织化学检测。通过Kaplan-Meier方法评估分类变量对总生存期（OS）和无进展生存期（PFS）等时间依赖性结局的影响。 结果：本研究纳入30例患者（男性19例，女性11例），中位年龄59.8岁（范围40.2-69.1岁）。所有患者均接受手术，随后进行替莫唑胺同步放化疗及辅助治疗。14例患者（47%）存在MGMT甲基化，16例患者（53%）为MGMT非甲基化。在TME中，肿瘤内和血管周围的CD4+淋巴细胞总体绝对百分比显著高于CD8+淋巴细胞（p=0.02）。低密度CD4+淋巴细胞（≤10%）被发现是GBM预后的有利因素（p=0.02）。MGMT甲基化与非甲基化肿瘤患者表现出不同的TME组成：在MGMT非甲基化肿瘤中，血管周围CD8+淋巴细胞（p=0.002）、肿瘤内CD8+淋巴细胞（p=0.0024）和血管周围CD4+淋巴细胞（p=0.014）数量显著更高。在4个肿瘤（13.3%）中观察到肿瘤细胞表面表达PD-L1，在9个肿瘤（30%）中观察到浸润T淋巴细胞表达PD1，且主要呈血管周围分布。 结论：MGMT甲基化与非甲基化肿瘤呈现不同的免疫特征，这可能反映了这两类肿瘤不同的生物学特性。PD-L1在GBMIDH-wt患者中的表达仅限于小部分亚群。虽然我们发现低CD4+淋巴细胞密度（≤10%）与生存期存在显著关联，但由于本研究队列规模较小，CD4+淋巴细胞密度的预后价值仍需在大规模研究中验证。
Immunophenotypic Profile of Adult Glioblastoma IDH-Wildtype Microenvironment: A Cohort Study
肿瘤(癌症)患者之家