Mendoza-Naranjo Ariadna, Saéz Pablo J, Johansson C Christian, Ramírez Marcos, Mandakovic Dinka, Pereda Cristian, López Mercedes N, Kiessling Rolf, Sáez Juan C, Salazar-Onfray Flavio
Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
J Immunol. 2007 Jun 1;178(11):6949-57. doi: 10.4049/jimmunol.178.11.6949.
Previously, we found that human dendritic cells (hDCs) pulsed with a melanoma cell lysate (MCL) and stimulated with TNF-alpha (MCL/TNF) acquire a mature phenotype in vitro and are able to trigger tumor-specific immune responses when they are used in melanoma immunotherapy in patients. In this study, we describe that MCL/TNF induces gap junction (GJ)-mediated intercellular communications and promotes melanoma Ag transfer between ex vivo produced hDCs from melanoma patients. hDCs also exhibit increased expression of the GJ-related protein connexin 43, which contributes to GJ plaque formation after MCL/TNF stimulation. The addition of GJ inhibitors suppresses intercellular tumor Ag transfer between hDCs, thus reducing melanoma-specific T cell activation. In summary, we demonstrate that MCL/TNF-stimulated hDCs can establish functional GJ channels that participate in melanoma Ag transfer, facilitating Ag cross-presentation and an effective dendritic cell-mediated melanoma-specific T cell response. These results suggest that GJs formed between hDCs used in cancer vaccination protocols could be essentials for the establishment of a more efficient antitumor response.
此前，我们发现用黑色素瘤细胞裂解物（MCL）脉冲处理并用肿瘤坏死因子-α（TNF-α）刺激的人树突状细胞（hDCs）在体外获得成熟表型，并且当它们用于患者的黑色素瘤免疫治疗时能够引发肿瘤特异性免疫反应。在本研究中，我们描述了MCL/TNF诱导间隙连接（GJ）介导的细胞间通讯，并促进黑色素瘤患者体外产生的hDCs之间的黑色素瘤抗原转移。hDCs还表现出GJ相关蛋白连接蛋白43的表达增加，这有助于MCL/TNF刺激后GJ斑块的形成。添加GJ抑制剂可抑制hDCs之间的细胞间肿瘤抗原转移，从而减少黑色素瘤特异性T细胞活化。总之，我们证明MCL/TNF刺激的hDCs可以建立参与黑色素瘤抗原转移的功能性GJ通道，促进抗原交叉呈递和有效的树突状细胞介导的黑色素瘤特异性T细胞反应。这些结果表明，癌症疫苗接种方案中使用的hDCs之间形成的GJ可能是建立更有效的抗肿瘤反应的关键。
