Induction of dendritic cell maturation in the skin microenvironment by soluble factors derived from colon carcinoma

• Published in: Human vaccines & immunotherapeutics Vol. 10; no. 6; pp. 1622 - 1632
• Main Authors: Lindenberg, Jelle J, van de Ven, Rieneke, Oosterhoff, Dinja, Sombroek, Claudia C, Lougheed, Sinéad M, Stam, Anita GM, Koenen, Hans JPM, van den Eertwegh, Alfons JM, Scheper, Rik J, de Gruijl, Tanja D
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 2014; Landes Bioscience
• Subjects: Animals; Carcinoma - chemistry; Cell Differentiation - drug effects; Cell Line; Cell Movement - drug effects; colon cancer; Colonic Neoplasms - chemistry; COX; dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; GM-CSF; Immunologic Factors - isolation & purification; Immunologic Factors - metabolism; Mice; prostaglandin; Research Paper; skin; Skin - drug effects; Skin - immunology; skin; dendritic cells; GM-CSF; prostaglandin; COX; colon cancer
• ISSN: 2164-5515; 2164-554X
• DOI: 10.4161/hv.28548

Autologous tumor cell-based vaccines provide a wide range of tumor antigens and personalized neo-epitopes based on individual tumors' unique antigenic mutanome signatures. However, tumor-derived factors may hamper in situ maturation of dendritic cells (DC) and thus interfere with the generation of effective anti-tumor immunity. As the skin is a preferred site for tumor vaccine delivery, we investigated the influence of primary colon carcinoma-derived soluble factors on the maturation state of migrating DC in a human skin explant model. Primary tumor-derived supernatants (TDSN) enhanced the phenotypic maturation state of skin-emigrated DC, resulting in an increased T-cell stimulatory ability in an allogeneic mixed leukocyte response. In case of monocyte-derived DC a similar TDSN-induced maturation induction was found to entirely depend on cyclooxygenase (COX)-regulated prostaglandins. In contrast, the increase in skin-emigrated DC maturation was completely prostaglandin-independent, as evidenced by the inability of the COX inhibitor indomethacin to abrogate this TDSN-induced effect. Although TDSN conditioning affected a drop in IL-12p70 release by the skin-emigrated DC and induced a predominant Th17/Th22 transcriptional profile in subsequently stimulated T-cells, Th cell subset differentiation, as assessed by intracellular cytokine expression upon polyclonal priming and re-stimulation, was not affected. Comparative analysis of phenotypic and transcriptional profiles suggests that the observed maturational effects in skin-derived DC may have been induced by tumor-derived GM-CSF. In conclusion, soluble factors derived from whole-cell colon tumor vaccines will not negatively impact DC migration and maturation in human skin, but rather induce DC maturation that will facilitate the priming of a poly-functional Th cell response.