title: Expression of LIGHT/TNFSF14 combined with vaccination against human papillomavirus Type 16 E7 induces significant tumor regression.
abstract: 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.
authors.affiliation: Department of Molecular Microbiology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Shreya
authors.initials: S
authors.lastname: Kanodia
authors.forename: Diane M
authors.initials: DM
authors.lastname: Da Silva
authors.forename: Tigran
authors.initials: T
authors.lastname: Karamanukyan
authors.forename: Lies
authors.initials: L
authors.lastname: Bogaert
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
mesh_terms: 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
chemical_list: 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
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