Gene expression profiling reveals similarities between the in vitro and in vivo responses of immune effector cells to IFN-alpha.
OBJECTIVE
The precise molecular targets of IFN-alpha therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-alpha would be similar to the in vivo response to treatment with high-dose IFN-alpha.


METHODS
The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-alpha were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-alpha.


RESULTS
Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-alpha in vitro for 18 hours (>2-fold, P < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-alpha-treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (n = 13) receiving high-dose IFN-alpha-2b (20 MU/m(2) i.v.) revealed significant up-regulation (>2-fold) of 21 genes (P < 0.001). Also, the gene expression profile of in vitro IFN-alpha-stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-alpha therapy.


CONCLUSIONS
This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-alpha and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-alpha immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-alpha may be a useful predictor of the in vivo response of immune cells to IFN-alpha immunotherapy.
Zimmerer
Jason M
JM
Integrated Biological Sciences Graduate Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Lesinski
Gregory B
GB
Ruppert
Amy S
AS
Radmacher
Michael D
MD
Noble
Carl
C
Kendra
Kari
K
Walker
Michael J
MJ
Carson
William E
WE
D001782:Blood Donors; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology*; D046228:Microarray Analysis; D009000:Monocytes / Q000276:immunology; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology; D015533:Transcriptional Activation; D015854:Up-Regulation
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins
J Exp Med. 1995 Jul 1;182(1):155-62
7540647
Nature. 1985 Jun 20-26;315(6021):672-6
3925348
J Clin Oncol. 2006 Jul 1;24(19):3164-71
16809739
Clin Cancer Res. 2003 Jun;9(6):2022-31
12796364
N Engl J Med. 2006 Feb 16;354(7):758-60
16481646
World J Gastroenterol. 2004 Jun 15;10(12):1740-5
15188497
J Immunol. 2003 Jun 1;170(11):5373-81
12759411
Cell Mol Immunol. 2006 Aug;3(4):255-61
16978533
J Interferon Cytokine Res. 2003 Jan;23(1):3-10
12639293
J Transl Med. 2005 Jun 13;3:24
15953390
J Clin Invest. 2002 Oct;110(7):983-92
12370276
Nat Genet. 2003 Dec;35(4):341-8
14608356
Clin Cancer Res. 2002 Aug;8(8):2480-7
12171873
J Immunol. 2007 Apr 15;178(8):4832-45
17404264
Int J Cancer. 1982 Dec 15;30(6):813-20
6186614
Nature. 2005 Mar 10;434(7030):243-9
15665823
Int J Cancer. 1982 Dec 15;30(6):821-5
6186615
J Clin Invest. 2003 Jul;112(2):170-80
12865406
Hepatology. 2003 May;37(5):1180-8
12717400
J Virol. 2000 May;74(9):4174-82
10756030
Blood. 2007 Feb 1;109(3):1113-22
17018853
Biochemistry. 1997 Jan 28;36(4):856-63
9020784
Cytokine Growth Factor Rev. 2002 Apr;13(2):119-34
11900988
Int J Cancer. 1994 May 15;57(4):604-11
8181864
Eur J Immunol. 2006 Aug;36(8):2046-60
16856207
J Virol. 2003 Jun;77(11):6367-75
12743294
Cancer Immunol Immunother. 2005 Sep;54(9):815-25
15668815
Br J Dermatol. 2003 Jun;148(6):1115-24
12828737
Nature. 2005 Apr 7;434(7034):772-7
15800576
Hepatology. 2003 Mar;37(3):610-21
12601359
J Immunol. 1999 Oct 15;163(8):4109-13
10510345
J Leukoc Biol. 1997 Mar;61(3):246-57
9060447
J Invest Dermatol. 1990 Dec;95(6 Suppl):231S-237S
2124247
Cytogenet Cell Genet. 1996;74(4):255-8
8976378
Int J Cancer. 1990 Sep 15;46(3):468-74
2394514
J Immunol. 2002 Apr 1;168(7):3195-204
11907072