CTLA-4 blockade augments human T lymphocyte-mediated suppression of lung tumor xenografts in SCID mice
CTLA-4 blockade augments human T lymphocyte-mediated suppression of lung tumor xenografts in SCID mice
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DOI：
10.1007/s00262-005-0668-3
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发表时间：
2005-10-01
影响因子：
5.8
通讯作者：
Bankert, RB
中科院分区：
文献类型：
--
作者：
Sabel, MS;Hess, SD;Bankert, RB
其他人使用可移植的鼠肿瘤模型的先前研究已经证明，阻断CTLA-4与B7相互作用的抗体的施用可以引起已建立的肿瘤的消除，并且肿瘤抑制由T细胞和/或表达NK 1.1的细胞介导。我们实验室的研究已经在人/严重联合免疫缺陷（SCID）小鼠嵌合模型中建立了自体外周血白细胞（PBL）可以以PBL剂量依赖性方式抑制肿瘤异种移植物的生长，并且这种抑制依赖于患者的T和NK细胞。使用这种人/小鼠嵌合模型，我们试图确定CTLA-4的抗体阻断是否会增强患者PBL的抗肿瘤应答。首先重要的是确定在SCID模型中观察到的肿瘤抑制是否依赖于CD 28/B7共刺激。用人CTLA-4-IG融合蛋白阻断B7完全消除了淋巴细胞介导的肿瘤抑制，证实在该模型中肿瘤抑制依赖于CD 28/B7共刺激。使用两种不同的CTLA-4特异性单克隆抗体，我们观察到CTLA-4阻断显著增强了PBL和肿瘤细胞共移植小鼠中人淋巴细胞介导的肿瘤抑制。在同种异体环境（其中PBL相对于肿瘤是同种异体的）和自体环境（其中PBL和肿瘤来自同一患者）中均观察到这种增强。这些结果支持了这样的观点，即人抗肿瘤免疫应答可以通过阻断CTLA-4和B7之间的相互作用来增强（体内）。
Previous studies by others using transplantable murine tumor models have demonstrated that the administration of antibodies that block CTLA-4 interaction with B7 can provoke the elimination of established tumors, and that the tumor suppression is mediated by T-cells and/or cells expressing NK1.1. Studies from our lab have established in a human/severe combined immunodeficient (SCID) mouse chimeric model that autologous peripheral blood leukocytes (PBL) can suppress the growth of tumor xenografts in a PBL dose-dependent fashion, and that this suppression is dependent upon the patient's T and NK cells. Using this human/mouse chimeric model, we sought to determine whether an antibody blockade of CTLA-4 would enhance the anti-tumor response of a patient's PBL. It was first important to determine whether the tumor suppression observed in the SCID model was dependent upon CD28/B7 co-stimulation. Blockade of B7 with a human CTLA-4-Ig fusion protein completely abrogated the lymphocyte-mediated tumor suppression, confirming in this model that tumor suppression is dependent upon a CD28/B7 co-stimulation. Using two different CTLA-4 specific monoclonal antibodies, we observed that CTLA-4 blockade significantly enhanced the human lymphocyte-mediated tumor suppression in mice co-engrafted with PBL and tumor cells. This enhancement was observed in both an allogeneic setting (in which the PBL were allogeneic with respect to the tumor) and an autologous setting (in which the PBL and tumor were from the same patient). These results sustain the notion that human anti-tumor immune response can be augmented (in vivo) by blocking the interaction between CTLA-4 and B7.