title: Induction of dendritic cell maturation in the skin microenvironment by soluble factors derived from colon carcinoma.
abstract: 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.
authors.affiliation: Department of Medical Oncology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Jelle J
authors.initials: JJ
authors.lastname: Lindenberg
authors.affiliation: Department of Medical Oncology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Rieneke
authors.initials: R
authors.lastname: van de Ven
authors.affiliation: Department of Medical Oncology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Dinja
authors.initials: D
authors.lastname: Oosterhoff
authors.affiliation: Department of Pathology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Sombroek
authors.affiliation: Department of Medical Oncology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Lougheed
authors.affiliation: Department of Pathology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Anita G M
authors.initials: AG
authors.lastname: Stam
authors.affiliation: Laboratory of Medical Immunology; Department of Laboratory Medicine; Radboud University Nijmegen Medical Centre; Nijmegen, The Netherlands.
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.affiliation: Department of Medical Oncology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.affiliation: Department of Pathology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.affiliation: Department of Medical Oncology; VU University medical center; De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000737:chemistry*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000737:chemistry*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D007155:Immunologic Factors / Q000302:isolation & purification / Q000378:metabolism*; D051379:Mice; D012867:Skin / Q000187:drug effects / Q000276:immunology*
chemical_list: D007155:Immunologic Factors
keywords: COX; GM-CSF; colon cancer; dendritic cells; prostaglandin; skin
references.citation: PLoS One. 2013 Jul 18;8(7):e70237
references.pmid: 23875023
references.citation: J Exp Med. 1999 Nov 15;190(10):1417-26
references.pmid: 10562317
references.citation: Cancer Res. 1998 Oct 1;58(19):4245-9
references.pmid: 9766645
references.citation: Br J Cancer. 2003 Aug 4;89(3):533-8
references.pmid: 12888826
references.citation: Lancet. 1999 Jan 30;353(9150):345-50
references.pmid: 9950438
references.citation: J Leukoc Biol. 2005 Aug;78(2):319-24
references.pmid: 15809288
references.citation: Immunobiology. 2006;211(6-8):651-61
references.pmid: 16920504
references.citation: J Pathol. 2003 Jun;200(2):255-68
references.pmid: 12754747
references.citation: J Immunother. 2001 Mar-Apr;24(2):130-7
references.pmid: 11265770
references.citation: J Immunol. 2002 Nov 1;169(9):5322-31
references.pmid: 12391253
references.citation: J Immunol. 1999 Jun 1;162(11):6378-83
references.pmid: 10352250
references.citation: J Invest Dermatol. 1996 Jun;106(6):1293-9
references.pmid: 8752673
references.citation: Adv Exp Med Biol. 1997;417:363-7
references.pmid: 9286387
references.citation: Clin Cancer Res. 2005 Apr 1;11(7):2576-82
references.pmid: 15814636
references.citation: Nat Immunol. 2001 Nov;2(11):1010-7
references.pmid: 11590405
references.citation: Nat Rev Drug Discov. 2013 Jul;12(7):504
references.pmid: 23787957
references.citation: Oncoimmunology. 2012 Aug 1;1(5):751-753
references.pmid: 22934271
references.citation: Arch Dermatol Res. 2000 Sep;292(9):437-45
references.pmid: 11000287
references.citation: Cancer Immunol Immunother. 2004 Nov;53(11):978-86
references.pmid: 15197496
references.citation: BMC Cancer. 2013 Feb 05;13:59
references.pmid: 23379788
references.citation: PLoS One. 2011;6(11):e27944
references.pmid: 22125641
references.citation: EMBO J. 2013 Jan 23;32(2):194-203
references.pmid: 23258224
references.citation: Cancer Res. 2013 Jan 1;73(1):395-405
references.pmid: 23108143
references.citation: Clin Cancer Res. 2012 Feb 1;18(3):882-9
references.pmid: 22156611
references.citation: Hum Pathol. 2004 Nov;35(11):1392-6
references.pmid: 15668897
references.citation: Clin Exp Immunol. 2003 May;132(2):352-9
references.pmid: 12699428
references.citation: J Immunol. 2000 Feb 1;164(3):1269-76
references.pmid: 10640740
references.citation: Cancer Res. 2001 Apr 1;61(7):3096-104
references.pmid: 11306493
references.citation: J Immunol. 2001 Apr 1;166(7):4465-72
references.pmid: 11254702
references.citation: J Immunol. 2002 May 1;168(9):4333-43
references.pmid: 11970975
references.citation: Nat Rev Immunol. 2002 Mar;2(3):151-61
references.pmid: 11913066
references.citation: Nat Rev Immunol. 2004 Dec;4(12):941-52
references.pmid: 15573129
references.citation: Br J Cancer. 2001 Dec 14;85(12):1944-51
references.pmid: 11747338
references.citation: J Immunol. 2011 Apr 1;186(7):4388-95
references.pmid: 21357259
references.citation: Clin Cancer Res. 2006 May 1;12(9):2826-33
references.pmid: 16675577
references.citation: Blood. 2005 Oct 1;106(7):2375-81
references.pmid: 15947091
references.citation: Trends Immunol. 2003 Mar;24(3):108-11
references.pmid: 12615202
references.citation: Cancer Res. 2008 Feb 1;68(3):889-92
references.pmid: 18245491
references.citation: Blood. 2008 Sep 15;112(6):2340-52
references.pmid: 18617638
references.citation: J Immunol. 2002 Mar 1;168(5):2255-63
references.pmid: 11859113
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Oncoimmunology. 2012 Aug 1;1(5):768-769
references.pmid: 22934277
references.citation: Cancer Res. 2012 Mar 1;72(5):1081-91
references.pmid: 22237626
references.citation: Adv Exp Med Biol. 1997;417:125-8
references.pmid: 9286349
references.citation: PLoS One. 2013;8(1):e52875
references.pmid: 23341914
references.citation: J Immunol. 2006 Jun 15;176(12):7232-42
references.pmid: 16751366