Type 2 Bias of T Cells Expanded from the Blood of Melanoma Patients Switched to Type 1 by IL-12p70 mRNA-Transfected Dendritic Cells
Type 2 Bias of T Cells Expanded from the Blood of Melanoma Patients Switched to Type 1 by IL-12p70 mRNA-Transfected Dendritic Cells
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DOI：
10.1158/0008-5472.can-08-0900
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Bhardwaj, Nina
中科院分区：
文献类型：
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作者：
Minkis, Kira;Kavanagh, Daniel G.;Bhardwaj, Nina
黑色素瘤患者可能在血液和肿瘤浸润性淋巴细胞中表现出T(H)2偏斜的细胞因子谱。因此，诱导有益的T(H)1型肿瘤特异性免疫反应的治疗是非常可取的。树突状细胞(DC)被广泛用作癌症的免疫佐剂。在给药前，DC通常在重组细胞因子[IL-1β、肿瘤坏死因子α和IL-6]和前列腺素E-2(PGE(2))的鸡尾酒中诱导成熟，前列腺素E-2是为了保持DC迁移到引流淋巴结的能力而添加的。然而，PGE(2)抑制IL-12p70的产生，IL-12p70是分化T(H)1反应所必需的细胞因子。本研究将IL-12p70基因导入人DC，检测其改变黑色素瘤患者外周血T细胞T(H)2型偏向的能力。转基因DC分泌高水平的生物活性IL-12p70，其能力包括增强自然杀伤细胞活性，通过减少IL-4和IL-5而在同种异体混合淋巴细胞反应中歪曲T(H)1反应，以及启动CD8(+)T细胞对黑色素瘤相关抗原Melan A/Mart-1的反应。此外，从黑色素瘤患者的血液中体外启动的T细胞株显示出强烈的2型偏斜，而自体DC的IL-12p70转基因显著逆转了这种偏斜。因此，IL-12p70的临床DC制剂可以增强1型抗肿瘤反应，从而有助于有效的基于免疫的治疗。[癌症资源2008；68(22)：9441-50]
Melanoma patients may exhibit a T(H)2-skewed cytokine profile within blood and tumor-infiltrating lymphocytes. Therapies that induce beneficial T(H)1-type tumor-specific immune responses, therefore, are highly desirable. Dendritic cells (DC) are widely used as immune adjuvants for cancer. Before their administration, DC are generally induced to mature with a cocktail of recombinant cytokines [interleukin (IL)-1 beta, tumor necrosis factor alpha, and IL-6] and prostaglandin E-2 (PGE(2)), which is added to preserve the ability of DC to migrate to draining lymph nodes. However, PGE(2) suppresses the production of IL-12p70, a cytokine essential for differentiation of T(H)1 responses. In this study, human DC were transfected with IL-12p70 mRNA and tested for their ability to alter the T(H)2 type bias manifested by blood T cells of patients with melanoma. Transfected DC secreted high levels of bioactive IL-12p70, as indicated by their capacity to enhance natural killer cell activity, skew T(H)1 responses in allogeneic mixed lymphocyte reactions through reduction of IL-4 and IL-5, and prime CD8(+) T cells to the melanoma-associated antigen Melan A/MART-1. Furthermore, T-cell lines primed in vitro from the blood of melanoma patients showed strong type 2 skewing that was dramatically reversed by IL-12p70 transfection of autologons DC. Thus, IL-12p70 transfection of clinical DC preparations may enhance type 1 antitumor responses and may thereby contribute to effective immune-based therapy. [Cancer Res 2008;68(22):9441-50]