Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells.
Despite the crucial roles dendritic cells (DC) play in host immunity against cancer, the pharmacologic effects of many chemotherapeutic agents have remained mostly unknown. We recently developed a DC biosensor clone by engineering the stable murine DC line XS106 to express the yellow fluorescent protein (YFP) gene under the control of interleukin (IL)-1beta promoter. In this study, the resulting XS106 pIL1-YFP DC clone was used to screen 54 anticancer drugs. Each drug was tested at five concentrations (0.1-10 micromol/L) for its effects on YFP expression, cell viability, and granulocyte macrophage colony-stimulating factor-dependent growth. Our unbiased systematic screening unveiled a striking heterogeneity among the tested anticancer drugs in their effects on the three functional variables. Interestingly, 15 drugs induced significant YFP expression at subcytotoxic concentrations and were thus categorized as "DC-stimulatory" anticancer drugs. These drugs were subsequently found to induce at least one of the characteristic maturational changes in mouse bone marrow-derived DCs. For example, vinblastine, a prototypic drug of this class, induced the production of IL-1beta, IL-6, and IL-12, increased surface expression of CD40, CD80, CD86, and MHC class II, and augmented T cell-stimulatory capacity of DCs. Not only do these results illustrate the differential pharmacologic effects of commonly used chemotherapeutic agents on DCs, they may also provide a conceptual framework for rationale-based selection and combination of anticancer drugs for clinical application.
Tanaka
Hiroaki
H
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Matsushima
Hironori
H
Mizumoto
Norikatsu
N
Takashima
Akira
A
D000818:Animals; D000970:Antineoplastic Agents / Q000145:classification* / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000032:analysis; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D011401:Promoter Regions, Genetic; D014162:Transfection
D000970:Antineoplastic Agents; D016207:Cytokines; D053583:Interleukin-1beta; D008164:Luminescent Proteins
Nat Rev Immunol. 2008 Jan;8(1):59-73
18097448
Nat Med. 1999 Aug;5(8):930-7
10426318
J Exp Med. 1995 Aug 1;182(2):389-400
7629501
Blood. 2007 Jun 1;109(11):4839-45
17299090
Blood. 2004 Oct 15;104(8):2235-46
15231572
Nat Rev Immunol. 2005 Apr;5(4):296-306
15803149
Nat Rev Cancer. 2005 May;5(5):397-405
15864281
J Immunol. 1982 Dec;129(6):2816-25
6890568
Cancer Res. 2006 Jun 1;66(11):5527-36
16740684
J Exp Med. 1973 Mar 1;137(3):660-74
4144033
J Exp Med. 2005 Dec 19;202(12):1691-701
16365148
Nat Rev Cancer. 2004 Apr;4(4):253-65
15057285
Transplantation. 1984 Jun;37(6):600-5
6427998
Cell Immunol. 1978 Jul;38(2):276-85
209902
Neoplasma. 1973;20(3):239-42
4725513
J Clin Invest. 1998 Jan 15;101(2):429-41
9435316
J Immunol. 1976 Sep;117(3):1015-22
956646
Blood. 2005 Nov 1;106(9):3082-9
16002424
Cancer Res. 2006 Jan 15;66(2):951-9
16424030
Blood. 1990 Jul 15;76(2):307-11
1695108
Nat Rev Cancer. 2005 Apr;5(4):263-74
15776005
J Immunol. 1999 Jun 1;162(11):6811-8
10352302
J Invest Dermatol. 2007 Jun;127(6):1543-6
17301837
Nature. 2002 Aug 29;418(6901):983-8
12198548
Science. 1973 Jul 13;181(4095):171-3
4541240
Cell Death Differ. 2008 Jan;15(1):39-50
17948027
Eur J Immunol. 2004 Feb;34(2):336-44
14768038
Annu Rev Immunol. 2004;22:329-60
15032581
Nat Med. 2002 Apr;8(4):358-65
11927941
Int Arch Allergy Appl Immunol. 1976;52(1-4):257-65
797670
J Immunol. 2002 Oct 1;169(7):3555-64
12244145
Nature. 2007 Sep 27;449(7161):419-26
17898760