PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model
PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model
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DOI：
10.1182/blood-2009-03-206672
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发表时间：
2009-08-20
期刊：
影响因子：
20.3
通讯作者：
Kline, Justin
中科院分区：
文献类型：
--
作者：
Zhang, Long;Gajewski, Thomas F.;Kline, Justin
实体瘤微环境中的负调控机制抑制抗肿瘤T细胞功能，导致逃避免疫攻击。一种抑制机制是上调肿瘤或基质细胞上表达的程序性死亡配体1（PD-L1），其与活化T细胞上的程序性死亡-1（PD-1）结合。PD-1/PD-L1结合导致抗肿瘤T细胞应答减少，并与鼠和人实体癌的不良结局相关。与实体瘤中的可用数据相反，关于PD-1/PD-L1通路参与造血系统癌症（如急性髓性白血病（AML））的免疫逃逸知之甚少。为了研究这一假设，我们使用了小鼠白血病C1498。当静脉内转移时，C1498细胞进行性生长并且明显地逃避免疫破坏。在体外生长的C1498细胞上发现低水平的PD-L1表达。然而，当在体内生长时，PD-L1表达在C1498细胞上上调。用C1498细胞激发的PD-1（-/-）小鼠产生了增强的抗肿瘤T细胞应答，血液和其他器官中的AML负荷降低，存活时间显著长于野生型小鼠。使用PD-L1阻断抗体获得了类似的结果。这些数据表明PD-1/PD-L1通路在恶性血液病免疫逃避中的重要性，为在白血病患者中靶向该通路的临床试验提供了理论基础。（血。2009; 114：1545-1552）
Negative regulatory mechanisms within the solid tumor microenvironment inhibit antitumor T-cell function, leading to evasion from immune attack. One inhibitory mechanism is up-regulation of programmed death-ligand 1 (PD-L1) expressed on tumor or stromal cells which binds to programmed death-1 (PD-1) on activated T cells. PD-1/PD-L1 engagement results in diminished antitumor T-cell responses and correlates with poor outcome in murine and human solid cancers. In contrast to available data in solid tumors, little is known regarding involvement of the PD-1/PD-L1 pathway in immune escape by hematopoietic cancers, such as acute myeloid leukemia (AML). To investigate this hypothesis, we used the murine leukemia, C1498. When transferred intravenously, C1498 cells grew progressively and apparently evaded immune destruction. Low levels of PD-L1 expression were found on C1498 cells grown in vitro. However, PD-L1 expression was up-regulated on C1498 cells when grown in vivo. PD-1(-/-) mice challenged with C1498 cells generated augmented antitumor T-cell responses, showed decreased AML burden in the blood and other organs, and survived significantly longer than did wild-type mice. Similar results were obtained with a PD-L1 blocking antibody. These data suggest the importance of the PD-1/PD-L1 pathway in immune evasion by a hematologic malignancy, providing a rationale for clinical trials targeting this pathway in leukemia patients. (Blood. 2009; 114: 1545-1552)