Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo
Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo
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DOI：
10.1073/pnas.95.16.9482
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发表时间：
1998-08-04
影响因子：
11.1
通讯作者：
Mulé, JJ
中科院分区：
文献类型：
--
作者：
Fields, RC;Shimizu, K;Mulé, JJ
树突状细胞(DC)作为抗原提呈细胞的高效特性增加了在荷瘤宿主中发现低水平的T细胞对免疫原性低的肿瘤的反应性的可能性，这些肿瘤实际上是通过其他方法无法检测到的。我们证明了小鼠骨髓来源的、细胞因子驱动的DC在体外和体内的能力，当与整个肿瘤裂解物脉冲冲击时，可以诱导出强大和特异的抗肿瘤反应。肿瘤裂解液致敏的DC刺激原始脾T细胞在体外产生肿瘤特异性增殖细胞因子释放和细胞溶解反应。此外，在两个不同品系的小鼠中，组织学上不同的肿瘤，S.C.注射含有完整肿瘤裂解物的DC有效地为这些动物做好准备，以拒绝随后对存活的亲本肿瘤细胞的致命挑战，并且值得注意的是，还介导了肺部转移数量的显著减少。肿瘤排斥反应依赖于宿主来源的CD8(+)T细胞，在较小程度上依赖于CD4(+)T细胞。排斥肿瘤小鼠的脾含有特定的前体细胞毒性T淋巴细胞，使用完整的肿瘤裂解物作为肿瘤相关抗原(S)的来源来冲击DC，绕过了其他方法遇到的一些限制，并提供了某些独特的优点，本文对此进行了讨论。这些数据是我们最近在成人和儿童癌症患者中启动了一项自体肿瘤裂解物致敏DC免疫的I期临床试验的基础。
The highly efficient nature of dendritic cells (DC) as antigen-presenting cells raises the possibility of uncovering in tumor-bearing hosts very low levels of T cell reactivity to poorly immunogenic tumors that are virtually undetectable by other means. Were, we demonstrate the in vitro and in vivo capacities of murine bone marrow-derived, cytokine-driven DC to elicit potent and specific anti-tumor responses when pulsed with whole tumor lysates. Stimulation of naive spleen-derived T cells by tumor lysate-pulsed DC generated tumor-specific proliferative cytokine release and cytolytic reactivities in vitro. In addition, in two separate strains of mice with histologically distinct tumors, s.c. injections of DC pulsed with whole tumor lysates effectively primed these animals to reject subsequent lethal challenges with viable parental tumor cells and, important to note, also mediated significant reductions in the number of metastases established in the lungs. Tumor rejection depended an host-derived CD8(+) T cells and, to a lesser extent, CD4(+) T cells. Spleens from mice that had rejected their tumors contained specific precursor cytotoxic T lymphocytes, The use of whole tumor lysates as a source of tumor-associated antigen(s) for pulsing of DC circumvents several limitations encountered with other methods as well as provides certain distinct advantages, which are discussed. These data serve as rationale for our recent initiation of a phase I clinical trial of immunization with autologous tumor lysate-pulsed DC in adult and pediatric cancer patients.