PD-1 blockade enhances the vaccination-induced immune response in glioma
PD-1 blockade enhances the vaccination-induced immune response in glioma
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DOI：
10.1172/jci.insight.87059
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发表时间：
2016-07-07
期刊：
影响因子：
8
通讯作者：
Prins, Robert M.
中科院分区：
文献类型：
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作者：
Antonios, Joseph P.;Soto, Horacio;Prins, Robert M.
在临床前和临床研究中，用自体肿瘤裂解物进行DC疫苗接种已经证明了治疗胶质母细胞瘤（GBM）的有希望的结果。虽然疫苗似乎能够诱导T细胞浸润到肿瘤中，但主动疫苗接种在进行性生长的肿瘤中的有效性不太深刻。与此同时，许多研究已经确定了负性共刺激途径，如程序性死亡1/程序性死亡配体1（PD-1/PD-L1），作为肿瘤内免疫应答的相关介质。然而，对PD-1通路抑制的临床反应也各不相同。为了评估与已建立的神经胶质瘤的相关性，在颅内（i. c.）神经胶质瘤荷瘤小鼠。DC疫苗接种和PD-1 mAb阻断治疗均导致长期存活，而单独使用两种药物均未在具有较大已建立肿瘤的动物中诱导存活益处。这种生存益处完全依赖于CD 8（+）T细胞。此外，DC疫苗加PD-1 mAb阻断导致肿瘤浸润淋巴细胞（TIL）上整合素归巢和免疫记忆标志物的上调。在临床样品中，GBM患者中的DC疫苗接种与体内PD-1表达的上调相关，而在新鲜分离的TIL上离体阻断PD-1显著增强自体肿瘤细胞的细胞溶解。这些发现强烈表明PD-1/PD-L1通路在已建立的GBM对抗肿瘤活性疫苗接种的适应性免疫抗性中起重要作用，并为我们提供了这种联合治疗的临床转化的理论基础。
DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor-bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8(+) T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy.