Division of Molecular Pathology, Department of Pathology, China Medical University and Hospital, Taichung, Taiwan.
Department of Pathology, China Medical University and Beigang Hospital, Yunlin, Taiwan.
Front Immunol. 2018 May 29;9:727. doi: 10.3389/fimmu.2018.00727. eCollection 2018.
Glioblastoma (GBM) is the most common and lethal primary malignant glioma in adults. Dendritic cell (DC) vaccines have demonstrated promising results in GBM clinical trials. However, some patients do not respond well to DC therapy, with survival rates similar to those of conventional therapy. We retrospectively analyzed clinical and laboratory data to evaluate the factors affecting vaccine treatment.
Forty-seven patients with GBM were enrolled at China Medical University Hospital between 2005 and 2010 and divided into two subgroups. One subgroup of 27 patients received postsurgical adjuvant immunotherapy with autologous dendritic cell/tumor antigen vaccine (ADCTA) in conjunction with conventional treatment of concomitant chemoradiotherapy (CCRT) with temozolomide. The other 20 patients received only postsurgical conventional treatment without immunotherapy. Immunohistochemistry for CD45, CD4, CD8, programed death ligand 1 (PD-L1), and programed death 1 (PD-1) was performed on sections of surgical tumor specimens and peripheral blood mononuclear cells (PBMCs). Pearson's correlation, Cox proportional hazard model, and Kaplan-Meier analyses were performed to examine the correlations between the prognostic factors and survival rates.
Younger age (<57 years), gross total resection, and CCRT and PD-1 lymphocyte counts were significant prognostic factors of overall survival (OS) and progression-free survival (PFS) in the ADCTA group. Sex, CD45 lymphocyte count, CD4 or CD8 lymphocyte count, tumor PD-L1 expression, isocitrate dehydrogenase 1 mutation, and O6 methylguanine-DNA methyltransferase promoter methylation status were not significant factors in both groups. In the ADCTA group, patients with tumor-infiltrating lymphocytes (TILs) with a lower PD-1/CD8 ratio (≤0.21) had longer OS and PFS (median OS 60.97 months, < 0.001 and PFS 11.2 months, < 0.008) compared to those with higher PD-1/CD8 ratio (>0.21) (median OS 20.07 months, < 0.001 and PFS 4.43 months, < 0.008). Similar results were observed in patients' PBMCs; lymphocyte counts with lower PD-1/CD8 ratio (≤0.197) had longer OS and PFS. There was a significant correlation of PD-1/CD8 ratio between TILs and PBMCs (Pearson's correlation = 0.6002, < 0.001). By contrast, CD4, CD8, but PD-1, CD45 tumor-infiltrating lymphocytes have no impact on OS and PFS ( = 0.073 and = 0.249, respectively).
For patients receiving DC vaccine adjuvant therapy, better outcomes are predicted in patients with younger age, with TILs or PBMCs with lower PD-1/CD8 ratio, with gross tumor resection, and receiving CCRT.
胶质母细胞瘤（GBM）是成人中最常见和最致命的原发性恶性神经胶质瘤。树突状细胞（DC）疫苗在 GBM 临床试验中显示出了有前景的结果。然而，一些患者对 DC 治疗反应不佳，其生存率与常规治疗相似。我们回顾性分析了临床和实验室数据，以评估影响疫苗治疗的因素。
2005 年至 2010 年，中国医科大学附属医院共纳入 47 例 GBM 患者，并分为两组。其中 27 例患者接受了手术后辅助免疫治疗，即自体树突状细胞/肿瘤抗原疫苗（ADCTA）联合常规治疗，即同步放化疗联合替莫唑胺；另外 20 例患者仅接受手术后常规治疗，不进行免疫治疗。对手术肿瘤标本和外周血单个核细胞（PBMC）进行 CD45、CD4、CD8、程序性死亡配体 1（PD-L1）和程序性死亡 1（PD-1）的免疫组织化学染色。采用 Pearson 相关分析、Cox 比例风险模型和 Kaplan-Meier 分析，探讨预后因素与生存率之间的相关性。
在 ADCTA 组中，年龄较小（<57 岁）、大体全切除、同步放化疗和 PD-1 淋巴细胞计数是总生存期（OS）和无进展生存期（PFS）的显著预后因素。在两组中，性别、CD45 淋巴细胞计数、CD4 或 CD8 淋巴细胞计数、肿瘤 PD-L1 表达、异柠檬酸脱氢酶 1 突变和 O6-甲基鸟嘌呤-DNA 甲基转移酶启动子甲基化状态均不是显著因素。在 ADCTA 组中，肿瘤浸润淋巴细胞（TILs）中 PD-1/CD8 比值较低（≤0.21）的患者具有更长的 OS 和 PFS（中位 OS 60.97 个月，<0.001 和 PFS 11.2 个月，<0.008），而 PD-1/CD8 比值较高（>0.21）的患者则较短（中位 OS 20.07 个月，<0.001 和 PFS 4.43 个月，<0.008）。在患者的 PBMCs 中也观察到了类似的结果；PD-1/CD8 比值较低（≤0.197）的淋巴细胞计数具有更长的 OS 和 PFS。TILs 和 PBMCs 之间的 PD-1/CD8 比值存在显著相关性（Pearson 相关系数=0.6002，<0.001）。相比之下，CD4、CD8，但 PD-1、CD45 肿瘤浸润淋巴细胞对 OS 和 PFS 没有影响（=0.073 和=0.249，分别）。
对于接受 DC 疫苗辅助治疗的患者，年龄较小、TILs 或 PBMCs 中 PD-1/CD8 比值较低、肿瘤大体全切除和接受同步放化疗的患者具有更好的预后。
