Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors
Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors
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DOI：
10.1172/jci200214184
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发表时间：
2002-03-01
影响因子：
15.9
通讯作者：
Chen, LP
中科院分区：
文献类型：
--
作者：
Wilcox, RA;Flies, DB;Chen, LP
在动物模型中治疗晚期免疫原性差的肿瘤，被认为是迄今为止在癌症患者中观察到的最接近的模拟，仍然是癌症免疫治疗的主要挑战。我们以前报道过，在接受T细胞共刺激分子4-1BB（CD 137）的激动性mAb的小鼠中建立的肿瘤由于增强的肿瘤抗原特异性细胞毒性T淋巴细胞应答而消退。在这项研究中，我们证明了几种免疫原性差的肿瘤，包括C3肿瘤，TC-1肺癌和B16-F10黑色素瘤，一旦确定为实体瘤或转移瘤，抗4-1BB mAb治疗无效。我们提供的证据表明，免疫无知，而不是无能或删除，肿瘤抗原特异性CTL在肿瘤的进行性生长，防止共刺激抗4-1BB单抗。通过用肿瘤抗原衍生肽免疫来打破CTL无知，虽然不足以刺激治愈性CTL应答，但对于抗4-1BB mAb诱导CTL应答导致已建立的肿瘤消退是必要的。我们的研究结果为人类癌症的免疫治疗提供了一种新的方法。
Treatment of advanced, poorly immunogenic tumors in animal models, considered the closest simulation available thus far for conditions observed in cancer patients, remains a major challenge for cancer immunotherapy. We reported previously that established tumors in mice receiving an agonistic mAb to the T cell costimulatory molecule 4-1BB (CD 137) regress due to enhanced tumor antigen-specific cytotoxic T lymphocyte responses. In this study, we demonstrate that several poorly immunogenic tumors, including C3 tumor, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, are refractory to treatment by anti-4-1BB mAb. We provide evidence that immunological ignorance, rather than anergy or deletion, of tumor antigen-specific CTLs during the progressive growth of tumors prevents costimulation by anti-4-1BB mAb. Breaking CTL ignorance by immunization with a tumor antigen-derived peptide, although insufficient to stimulate a curative CTL response, is necessary for anti-4-1BB mAb to induce a CTL response leading to the regression of established tumors. Our results suggest a new approach for immunotherapy of human cancers.