NK1.1+ cells mediate the antitumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model.
Innate immune stimulation with Toll-like receptor (TLR) agonists is a proposed modality for immunotherapy of melanoma. Here, a TLR7/8 agonist, 3M-011, was used effectively as a single systemic agent against disseminated mouse B16-F10 melanoma. The investigation of the mechanism of antitumor action revealed that the agonist had no direct cytotoxic effects on tumor cells tested in vitro. In addition, 3M-011 retained its effectiveness in scid/B6 mice and scid/NOD mice, eliminating the requirement for T and B cells, but lost its activity in beige (bg/bg) and NK1.1-immunodepleted mice, suggesting a critical role for natural killer (NK) cells in the antitumor response. NK cytotoxicity was enhanced in vivo by the TLR7/8 agonist; this activation was long lasting, as determined by sustained expression of the activation marker CD69. Also, in human in vitro studies, 3M-011 potentiated NK cytotoxicity. TLR7/8-mediated NK-dependent antitumor activity was retained in IFN-alpha/beta receptor-deficient as well as perforin-deficient mice, while depletion of IFN-gamma significantly decreased the ability of 3M-011 to delay tumor growth. Thus, IFN-gamma-dependent functions of NK cell populations appear essential for cancer immunotherapy with TLR7/8 agonists.
Dumitru
Calin D
CD
Department of Pharmacology, 3M Pharmaceuticals, St Paul, MN 55144, USA. calin_dumitru@merck.com
Antonysamy
Mary A
MA
Gorski
Kevin S
KS
Johnson
Dave D
DD
Reddy
Laxma G
LG
Lutterman
Jody L
JL
Piri
Melissa M
MM
Proksch
Joel
J
McGurran
Sean M
SM
Egging
Elaine A
EA
Cochran
Felicia R
FR
Lipson
Kenneth E
KE
Tomai
Mark A
MA
Gullikson
Gary W
GW
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D011804:Quinolines / Q000627:therapeutic use*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*
C526116:3M 001; D000970:Antineoplastic Agents; D007093:Imidazoles; D016328:NF-kappa B; D011804:Quinolines; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D007371:Interferon-gamma
Biometrics. 1981 Jun;37(2):383-90
7272422
Nat Med. 2006 Feb;12(2):207-13
16444266
Immunopharmacol Immunotoxicol. 1999 Aug;21(3):565-82
10466080
J Exp Med. 2003 Apr 21;197(8):977-84
12695489
Science. 2004 Mar 5;303(5663):1529-31
14976261
J Immunol. 2002 Oct 15;169(8):4279-87
12370359
J Reprod Immunol. 2005 Dec;68(1-2):39-51
16309747
Cancer Res. 1980 Mar;40(3):614-9
6162552
Nat Rev Immunol. 2001 Nov;1(2):135-45
11905821
Annu Rev Immunol. 2005;23:275-306
15771572
Nat Immunol. 2001 Aug;2(8):675-80
11477402
Science. 2004 Mar 5;303(5663):1526-9
14976262
Int J Immunopharmacol. 1999 Jan;21(1):1-14
10411278
J Immunol. 1979 Nov;123(5):2168-73
489978
Nat Rev Drug Discov. 2006 Jun;5(6):471-84
16763660
J Immunol. 2006 Jan 1;176(1):248-55
16365416
Leukemia. 2007 Jan;21(1):53-60
17066089
Annu Rev Immunol. 2002;20:197-216
11861602
J Immunol. 2005 Feb 1;174(3):1259-68
15661881
J Immunol. 2001 Nov 1;167(9):5247-53
11673539
J Exp Med. 2003 Apr 21;197(8):967-76
12695488
Curr Opin Immunol. 2003 Oct;15(5):522-7
14499260
Drugs. 2006;66(1):15-29
16398566
Cancer Res. 2004 Aug 15;64(16):5850-60
15313929
Cancer Res. 2004 Jan 1;64(1):406-14
14729652
J Allergy Clin Immunol. 2006 May;117(5):979-87; quiz 988
16675322
Chem Immunol Allergy. 2005;86:120-135
15976491
J Immunol. 2005 Mar 1;174(5):2612-8
15728467
Clin Oncol (R Coll Radiol). 2001;13(6):466-9
11824888
Nat Rev Immunol. 2003 May;3(5):361-70
12766758
Cancer Res. 2004 Aug 1;64(15):5461-70
15289356
Cancer Res. 1992 Jul 1;52(13):3528-33
1377595
Cancer Res. 2006 Jun 1;66(11):5527-36
16740684
Cell. 1995 Mar 10;80(5):813-23
7889575
Cancer Res. 2006 Nov 1;66(21):10497-504
17079471
Nat Med. 2006 Feb;12(2):214-9
16444265
Cancer Res. 2004 Jan 15;64(2):757-64
14744795
Int Immunol. 2006 Jul;18(7):1115-26
16728430
Nat Immunol. 2002 Feb;3(2):196-200
11812998
Clin Cancer Res. 2001 Nov;7(11):3540-3
11705874
Eur J Immunol. 2001 Jun;31(6):1720-7
11385616
Cancer Res. 2001 Jul 15;61(14):5523-8
11454702
J Invest Dermatol. 2004 Feb;122(2):387-91
15009720
Endocr Relat Cancer. 2003 Jun;10(2):301-8
12790791
Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11284-8
7479980
Eur J Immunol. 2000 Sep;30(9):2507-15
11009083
Cell Immunol. 2002 Jul-Aug;218(1-2):74-86
12470615
FASEB J. 2006 May;20(7):982-4
16571772