Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme.
Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme.
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DOI：
10.3389/fimmu.2018.00727
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发表时间：
2018
影响因子：
7.3
通讯作者：
Cho DY
中科院分区：
文献类型：
--
作者：
Jan CI;Tsai WC;Harn HJ;Shyu WC;Liu MC;Lu HM;Chiu SC;Cho DY
胶质母细胞瘤（GBM）是成人中最常见和致命的原发性恶性胶质瘤。树突状细胞 (DC) 疫苗在 GBM 临床试验中显示出有希望的结果。然而，一些患者对 DC 治疗反应不佳，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 年间，中国医科大学附属医院纳入了 47 名新发 GBM 患者，分为两个亚组。其中一组 27 名患者接受了自体树突状细胞/肿瘤抗原疫苗 (ADCTA) 的术后辅助免疫治疗以及替莫唑胺伴随放化疗 (CCRT) 的常规治疗。另外20名患者仅接受术后常规治疗，未接受免疫治疗。对手术肿瘤标本和外周血单核细胞 (PBMC) 切片进行 CD45、CD4、CD8、程序性死亡配体 1 (PD-L1) 和程序性死亡 1 (PD-1) 的免疫组织化学分析。采用 Pearson 相关性、Cox 比例风险模型和 Kaplan-Meier 分析来检查预后因素与生存率之间的相关性。较低的年龄（<57岁）、大体全切除以及CCRT和PD-1+淋巴细胞计数是ADCTA组中总生存期（OS）和无进展生存期（PFS）的重要预后因素。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在两组中都不是显着因素。在 ADCTA 组中，与 PD-1+/CD8+ 比率较高的患者相比，PD-1+/CD8+ 比率较低（≤0.21）的肿瘤浸润淋巴细胞（TIL）患者的 OS 和 PFS 更长（中位 OS 60.97 个月，P<0.001，PFS 11.2 个月，P<0.008）。比率 (>0.21)（中位 OS 20.07 个月， P < 0.001，PFS 4.43 个月，P < 0.008）。在患者的 PBMC 中也观察到了类似的结果； PD-1+/CD8+比率较低（≤0.197）的淋巴细胞计数具有较长的OS和PFS。 TIL和PBMC之间PD-1+/CD8+比值存在显着相关性（Pearson相关性R2 = 0.6002，P < 0.001）。相比之下，CD4−、CD8− 以及 PD-1+、CD45+ 肿瘤浸润淋巴细胞对 OS 和 PFS 没有影响（分别为 P = 0.073 和 P = 0.249）。对于接受 DC 疫苗辅助治疗的患者，年龄较小、TIL 或 PBMC 具有较低 PD-1+/CD8+ 比率、进行肉眼肿瘤切除和接受 CCRT 的患者预计会有更好的结果。
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 de novo 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, P < 0.001 and PFS 11.2 months, P < 0.008) compared to those with higher PD-1+/CD8+ ratio (>0.21) (median OS 20.07 months, P < 0.001 and PFS 4.43 months, P < 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 R2 = 0.6002, P < 0.001). By contrast, CD4−, CD8−, but PD-1+, CD45+ tumor-infiltrating lymphocytes have no impact on OS and PFS (P = 0.073 and P = 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.