title: Expression of anti-HVEM single-chain antibody on tumor cells induces tumor-specific immunity with long-term memory.
abstract: Genetic engineering of tumor cells to express immune-stimulatory molecules, including cytokines and co-stimulatory ligands, is a promising approach to generate highly efficient cancer vaccines. The co-signaling molecule, LIGHT, is particularly well suited for use in vaccine development as it delivers a potent co-stimulatory signal through the Herpes virus entry mediator (HVEM) receptor on T cells and facilitates tumor-specific T cell immunity. However, because LIGHT binds two additional receptors, lymphotoxin β receptor and Decoy receptor 3, there are significant concerns that tumor-associated LIGHT results in both unexpected adverse events and interference with the ability of the vaccine to enhance antitumor immunity. In order to overcome these problems, we generated tumor cells expressing the single-chain variable fragment (scFv) of anti-HVEM agonistic mAb on the cell surface. Tumor cells expressing anti-HVEM scFv induce a potent proliferation and cytokine production of co-cultured T cells. Inoculation of anti-HVEM scFv-expressing tumor results in a spontaneous tumor regression in CD4+ and CD8+ T cell-dependent fashion, associated with the induction of tumor-specific long-term memory. Stimulation of HVEM and 4-1BB co-stimulatory signals by anti-HVEM scFv-expressing tumor vaccine combined with anti-4-1BB mAb shows synergistic effects which achieve regression of pre-established tumor and T cell memory specific to parental tumor. Taken in concert, our data suggest that genetic engineering of tumor cells to selectively potentiate the HVEM signaling pathway is a promising antitumor vaccine therapy.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, 655 W. Baltimore St. BRB 9-051, Baltimore, MD, 21201, USA.
authors.forename: Jang-June
authors.initials: JJ
authors.lastname: Park
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, CA, USA.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Anand
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, 655 W. Baltimore St. BRB 9-051, Baltimore, MD, 21201, USA.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, 655 W. Baltimore St. BRB 9-051, Baltimore, MD, 21201, USA.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, 655 W. Baltimore St. BRB 9-051, Baltimore, MD, 21201, USA.
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Sakoda
authors.affiliation: Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kuramasu
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, 655 W. Baltimore St. BRB 9-051, Baltimore, MD, 21201, USA.|Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Strome
authors.affiliation: Department of Immunology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, 655 W. Baltimore St. BRB 9-051, Baltimore, MD, 21201, USA. ktamada@som.umaryland.edu.|Yamaguchi University Graduate School of Medicine, Ube, Japan. ktamada@som.umaryland.edu.|Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, USA. ktamada@som.umaryland.edu.
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005818:Genetic Engineering; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000276:immunology; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D016207:Cytokines; D053240:Receptors, Tumor Necrosis Factor, Member 14; D057127:Single-Chain Antibodies; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9