Expression of LIGHT/TNFSF14 combined with vaccination against human papillomavirus Type 16 E7 induces significant tumor regression.
LIGHT, a ligand for the lymphotoxin-beta receptor, establishes lymphoid-like tissues inside tumor sites and recruits naïve T cells into the tumor. However, whether these infiltrating T cells are specific for tumor antigens is not known. We hypothesized that therapy with LIGHT can expand functional tumor-specific CD8(+) T cells that can be boosted using HPV16E6E7-Venezuelan equine encephalitis virus replicon particles (HPV16-VRP) and that this combined therapy can eradicate human papillomavirus 16 (HPV16)-induced tumors. Our data show that forced expression of LIGHT in tumors results in an increase in expression of IFNgamma and chemoattractant cytokines such as interleukin-1a, MIG, and macrophage inflammatory protein-2 within the tumor and that this tumor microenvironment correlates with an increase in frequency of tumor-infiltrating CD8(+) T cells. Forced expression of LIGHT also results in the expansion of functional T cells that recognize multiple tumor antigens, including HPV16 E7, and these T cells prevent the outgrowth of tumors on secondary challenge. Subsequent boosting of E7-specific T cells by vaccination with HPV16-VRP significantly increases their frequency in both the periphery and the tumor and leads to the eradication of large well-established tumors, for which either treatment alone is not successful. These data establish the safety of Ad-LIGHT as a therapeutic intervention in preclinical studies and suggest that patients with HPV16(+) tumors may benefit from combined immunotherapy with LIGHT and antigen-specific vaccination.
Kanodia
Shreya
S
Department of Molecular Microbiology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033, USA.
Da Silva
Diane M
DM
Karamanukyan
Tigran
T
Bogaert
Lies
L
Fu
Yang-Xin
YX
Kast
W Martin
WM
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D004666:Encephalitis Virus, Venezuelan Equine / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy* / Q000821:virology; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology*; D030361:Papillomavirus Infections / Q000517:prevention & control / Q000821:virology; D010446:Peptide Fragments / Q000276:immunology; D012093:Replicon / Q000276:immunology*; D015996:Survival Rate; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism*; D014611:Vaccination
D019496:Cancer Vaccines; D050725:Papillomavirus E7 Proteins; D010446:Peptide Fragments; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma
Obstet Gynecol. 1986 May;67(5):665-9
3960438
J Clin Invest. 2001 Dec;108(12):1771-80
11748260
Am J Clin Pathol. 1994 Dec;102(6):768-74
7801889
Wound Repair Regen. 2008 Sep-Oct;16(5):602-14
19128255
Vaccine. 2000 Aug 15;19(1):142-53
10924796
Immunol Res. 1999;19(2-3):119-25
10493167
Br J Dermatol. 1986 Dec;115(6):681-92
3026431
Cancer Res. 1998 Jul 15;58(14):3087-93
9679975
Virology. 1997 Dec 22;239(2):389-401
9434729
Semin Cancer Biol. 2002 Feb;12(1):25-31
11926408
J Immunol. 2007 Aug 1;179(3):1960-8
17641063
Annu Rev Immunol. 2005;23:787-819
15771586
Eur J Immunol. 2002 Jul;32(7):1969-79
12115617
Virology. 1998 Nov 10;251(1):28-37
9813200
Nat Med. 2000 Mar;6(3):283-9
10700230
Cancer Res. 2007 Feb 1;67(3):1344-51
17283172
J Immunol. 2000 May 1;164(9):4558-63
10779757
Cancer Res. 2001 Nov 1;61(21):7861-7
11691804
Vaccine. 1999 Aug 6;17(23-24):3124-35
10462249
Mol Cancer. 2003 Apr 15;2:22
12740040
J Biol Chem. 2000 May 12;275(19):14307-15
10799510
Annu Rev Immunol. 1999;17:399-433
10358764
Eur J Immunol. 1995 Sep;25(9):2638-42
7589138
Nat Rev Immunol. 2003 Aug;3(8):642-55
12974479
Gynecol Oncol. 1990 Sep;38(3):377-82
2227552
Int J Cancer. 1992 Jan 2;50(1):45-8
1309459
Cancer Res. 2008 Feb 1;68(3):861-9
18245488
Int J Cancer. 2008 Jan 15;122(2):247-59
17973257
J Virol. 2000 Jan;74(1):371-8
10590126
Immunity. 1998 Jan;8(1):21-30
9462508
Science. 1999 Dec 10;286(5447):2098-102
10617422
Curr Opin Biotechnol. 1999 Oct;10(5):434-9
10508626
Vaccine. 2004 Jan 2;22(3-4):520-7
14670335
Int J Dermatol. 1988 Jun;27(5):322-6
2839432
Eur J Immunol. 1993 Sep;23(9):2242-9
7690326