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* Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile;
Department of Physiological Sciences, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile;
Department of Oncology and Pathology, Cancer Centre Karolinska, Stockholm, Sweden; and
Research Support Office, University of Chile Clinical Hospital, Santiago, Chile
Previously, we found that human dendritic cells (hDCs) pulsed with a melanoma cell lysate (MCL) and stimulated with TNF-
(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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Fund for the Promotion of Scientific and Technological Development (FONDEF DO2I1088), National Fund for Scientific and Technological Development (FONDECYT 1060935), Núcleo Milenio de Inmunología e Inmunoterapia P04/030-F, Research Support Office of Clinical Hospital of University of Chile, Swedish Cancer Society (Rolf Kiessling grants), Cancer Society of Stockholm, and European Network for the Identification and Validation of Antigens and Biomarkers in Cancer (Contract 6FP-CT-503306).
2 Address correspondence and reprint requests to Dr. Flavio Salazar-Onfray, Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Av. Independencia 1027 Santiago, Chile. E-mail address: Hfsalazar{at}inmunotron.med.uchile.cl
3 Abbreviations used in this paper: DC, dendritic cell; 
-Ga, 18 -glycyrrhetinic acid; Cx, connexin; GJ, gap junction; GJIC, GJ-mediated intercellular communication; hDC, human DC; MAA, melanoma-associated Ag; MCL, melanoma cell lysate.
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