Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes.
During disease progression in myelodysplastic syndromes (MDS), clonal blasts gain a more aggressive nature, whereas nonclonal immune cells become less efficient via an unknown mechanism. Using MDS cell lines and patient samples, we showed that the expression of an immunoinhibitory molecule, B7-H1 (CD274), was induced by interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) on MDS blasts. This induction was associated with the activation of nuclear factor-kappaB (NF-kappaB) and nearly completely blocked by an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). B7-H1(+) MDS blasts had greater intrinsic proliferative capacity than B7-H1(-) MDS blasts when examined in various assays. Furthermore, B7-H1(+) blasts suppressed T-cell proliferation and induced T-cell apoptosis in allogeneic cocultures. When fresh bone marrow samples from patients were examined, blasts from high-risk MDS patients expressed B7-H1 molecules more often compared with those from low-risk MDS patients. Moreover, MDS T cells often overexpressed programmed cell death 1 (PD-1) molecules that transmit an inhibitory signal from B7-H1 molecules. Taken together, these findings provide new insight into MDS pathophysiology. IFNgamma and TNFalpha activate NF-kappaB that in turn induces B7-H1 expression on MDS blasts. B7-H1(+) MDS blasts have an intrinsic proliferative advantage and induce T-cell suppression, which may be associated with disease progression in MDS.
Kondo
Asaka
A
Division of Hematology, Department of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan.
Yamashita
Taishi
T
Tamura
Hideto
H
Zhao
Wanhong
W
Tsuji
Takashi
T
Shimizu
Masumi
M
Shinya
Eiji
E
Takahashi
Hidemi
H
Tamada
Koji
K
Chen
Lieping
L
Dan
Kazuo
K
Ogata
Kiyoyuki
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D060890:B7-H1 Antigen; D001752:Blast Crisis; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
Blood. 2007 Aug 1;110(3):847-50
17412885
Mol Cell Biol. 1997 Nov;17(11):6746-54
9343439
J Biol Chem. 2004 Feb 6;279(6):4750-9
14630924
Br J Haematol. 1983 May;54(1):97-102
6221751
Leuk Res. 2009 Aug;33(8):1011-6
19344951
Leukemia. 1997 Dec;11(12):2049-54
9447819
Semin Oncol. 2005 Aug;32(4 Suppl 5):S31-5
16085015
Nat Med. 2002 Aug;8(8):793-800
12091876
Cancer Res. 2003 Oct 1;63(19):6501-5
14559843
Blood. 2002 Dec 1;100(12):3887-96
12393641
Nat Med. 1999 Dec;5(12):1365-9
10581077
Cancer Res. 2005 Feb 1;65(3):1089-96
15705911
J Immunol. 2001 May 15;166(10):6170-80
11342638
Blood. 2001 Mar 15;97(6):1809-16
11238124
Leukemia. 1996 Apr;10(4):662-8
8618444
Clin Cancer Res. 2007 Mar 15;13(6):1757-61
17363529
Blood. 2004 Oct 1;104(7):2124-33
15191948
Hematol Oncol Clin North Am. 1992 Jun;6(3):571-86
1613007
Eur J Immunol. 2007 Oct;37(10):2983-90
17899549
Mol Immunol. 2009 Jan;46(3):375-83
19081139
Int J Cancer. 2007 Aug 15;121(4):751-8
17415709
J Clin Invest. 2005 Oct;115(10):2625-32
16200195
Blood. 2006 Feb 1;107(3):1156-65
16223780
Immunol Rev. 2008 Aug;224:166-82
18759926
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17174-9
15569934
EMBO J. 1992 Nov;11(11):3887-95
1396582
J Exp Med. 2000 Oct 2;192(7):1027-34
11015443
Leuk Res. 1995 Sep;19(9):639-44
7564474
Eur J Haematol. 1991 Oct;47(4):277-81
1954986
Neoplasia. 2006 Mar;8(3):190-8
16611412
Leuk Res. 2009 Feb;33(2):326-31
18718658
Br J Haematol. 1994 Mar;86(3):562-7
8043438
Blood. 2008 Apr 1;111(7):3635-43
18223165
Clin Cancer Res. 2009 Feb 1;15(3):770-7
19188146
Blood. 1995 Jun 1;85(11):3183-90
7538820
Clin Cancer Res. 2004 Aug 1;10(15):5094-100
15297412
J Exp Med. 2003 May 5;197(9):1083-91
12719480
Clin Cancer Res. 2005 Aug 15;11(16):5708-17
16115907
Blood. 2000 Dec 1;96(12):3932-8
11090080
Oncogene. 2007 Jun 14;26(28):4071-83
17213804
Cancer Res. 2006 Apr 1;66(7):3381-5
16585157
Cancer Sci. 2009 Nov;100(11):2093-100
19703193
AAPS J. 2005 Mar 22;7(1):E14-9
16146335
Blood. 2006 Aug 1;108(3):1037-44
16574954
Leuk Res. 2007 Dec;31(12):1641-8
17485109
Blood. 1997 Mar 15;89(6):2079-88
9058730