Immune responses in the draining lymph nodes against cancer: Implications for immunotherapy
Immune responses in the draining lymph nodes against cancer: Implications for immunotherapy
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DOI：
10.1007/s10555-006-8503-7
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发表时间：
2006-06-01
影响因子：
9.2
通讯作者：
Maecker, Holden T.
中科院分区：
文献类型：
--
作者：
Shu, Suyu;Cochran, Alistair J.;Maecker, Holden T.
局部淋巴结是黑色素瘤转移的首要部位。前哨淋巴结（SN），在直接淋巴引流途径，通常窝藏第一转移，表现出显着抑制其能力，以响应抗原刺激。SN免疫的这种下调可能是其对肿瘤转移的易感性的基础，表明免疫系统在控制恶性肿瘤中的潜在作用。尽管SN中存在免疫功能障碍，但使用John韦恩癌症研究所开发的多价黑色素瘤疫苗进行全身性术后免疫治疗的II期试验显示，转移至区域淋巴结的黑色素瘤患者的5年总生存率有所改善。然而，大多数免疫治疗临床试验未能证明显著的临床应答，并且尚未建立对与临床应答相关的肿瘤相关抗原的免疫应答的分析。因此，检测方法的改进和疫苗设计的改进对于癌症免疫治疗的成功至关重要。树突状细胞（DC）的抗原呈递是启动T细胞免疫的最有效手段。基于树突状细胞的免疫疗法在过去十年中得到了大力尝试。为了提高肿瘤疫苗的免疫原性，我们最近通过电融合的方法制备了DC和肿瘤细胞的异核体。融合杂交体保留了其全部抗原呈递能力和所有天然肿瘤抗原。在临床前动物实验中，单次注射DC-肿瘤融合杂合体足以介导在肺、皮肤和脑中建立的肿瘤的消退。最有趣的是，成功的治疗需要将融合杂交体直接递送到淋巴器官如淋巴结中。目前正在进行一项临床试验，以测试融合杂交体治疗转移性黑色素瘤的免疫原性和治疗效果。
Regional lymph nodes are the first site for melanoma metastases. The sentinel node (SN), on the direct lymphatic drainage pathway, which usually harbors first metastases, demonstrates significant suppression in its ability to respond to antigenic stimulation. This down-regulation of SN immunity is likely the basis of its susceptibility to tumor metastases, suggesting a potential role of the immune system in the control of malignant tumors. Despite immune dysfunction in the SN, phase II trials of systemic post-operative immunotherapy with a polyvalent melanoma vaccine developed at the John Wayne Cancer Institute showed improved 5-year overall survival in patients with melanoma metastatic to regional nodes. However, most immunotherapy clinical trials have failed to demonstrate a significant clinical response, and analyses of immune responses to tumor-associated antigens that correlate clinical responses have not been established. Therefore, refinements in assay methodologies and improvements in vaccine designs are critical to the success of cancer immunotherapy. Antigen presentation by dendritic cells (DCs) is the most potent means to initiate a T cell immunity. Dendritic cell-based immunotherapies have been vigorously attempted in the past decade. To improve the immunogenicity of cancer vaccines, we recently generated heterokaryons of DCs and tumor cells by electrofusion. The fusion hybrids retained their full antigen-presenting capacity and all natural tumor antigens. In pre-clinical animal experiments, a single injection of the DC-tumor fusion hybrids was sufficient to mediate the regression of tumors established in the lung, skin and brain. Most interestingly, successful therapy required the delivery of fusion hybrids directly into lymphoid organs such as lymph nodes. A clinical trial is now being carried out to test the immunogenicity and therapeutic effects of fusion hybrids for the treatment of metastatic melanoma.