Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer.
Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer.
复制标题
DOI：
10.1158/0008-5472.can-10-0153
复制
发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Rosenberg SA
中科院分区：
文献类型：
--
作者：
Shrimali RK;Yu Z;Theoret MR;Chinnasamy D;Restifo NP;Rosenberg SA
基于过继细胞转移（ACT）的免疫疗法可以在动物模型和高达 70% 的转移性黑色素瘤患者中介导客观的癌症消退，但目前尚不清楚肿瘤脉管系统是否阻碍肿瘤特异性 T 细胞的流出，从而阻碍这种免疫疗法。据报道，破坏血管内皮生长因子 (VEGF) 与其受体 (VEGFR-2) 的促血管生成相互作用可以使肿瘤血管系统“正常化”，通过增加化疗药物向肿瘤间质的输送来增强化疗药物的疗效。因此，我们试图确定破坏 VEGF/VEGFR-2 信号传导是否可以增强 ACT 在小鼠癌症模型中的有效性。施用针对小鼠 VEGF 的抗体与 ACT 协同作用，可增强对已形成的血管化 B16 黑色素瘤的抑制 (p=0.009) 并提高生存率 (p=0.003)。在该模型中观察到抗 VEGFR-2 抗体与 ACT 结合的相加效应 (p=0.013)。抗 VEGF（而非抗 VEGFR-2）抗体显着增加了转移细胞向肿瘤的浸润。因此，通过破坏 VEGF/VEGFR-2 轴使肿瘤脉管系统正常化可以增加过继转移的 T 细胞外渗到肿瘤中，并改善基于 ACT 的免疫治疗。这些研究为探索抗血管生成药物与 ACT 联合治疗癌症患者提供了理论依据。
Adoptive cell transfer (ACT) – based immunotherapies can mediate objective cancer regression in animal models and in up to 70% of patients with metastatic melanoma but it remains unclear whether the tumor vasculature impedes the egress of tumor specific T cells thus hindering this immunotherapy. Disruption of the proangiogenic interaction of vascular endothelial growth factor (VEGF) with its receptor (VEGFR-2) has been reported to “normalize” tumor vasculature, enhancing the efficacy of chemotherapeutic agents by increasing their delivery to the tumor intersitium. We thus sought to determine whether disrupting VEGF/VEGFR-2 signaling could enhance the effectiveness of ACT in a murine cancer model. The administration of an antibody against mouse VEGF synergized with ACT to enhance inhibition of established, vascularised, B16 melanoma (p=0.009) and improve survival (p=0.003). Additive effects of an antibody against VEGFR-2 in conjunction with ACT were seen in this model (p=0.013). Anti VEGF, but not anti VEGFR-2, antibody significantly increased infiltration of transferred cells into the tumor. Thus, normalization of tumor vasculature through disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively transferred T cells into the tumor and improve ACT-based immunotherapy. These studies provide a rationale for the exploration of combining antiangiogenic agents with ACT for the treatment of patients with cancer.