title: Manipulating TLR Signaling Increases the Anti-tumor T Cell Response Induced by Viral Cancer Therapies.
abstract: The immune response plays a key role in enhancing the therapeutic activity of oncolytic virotherapies. However, to date, investigators have relied on inherent interactions between the virus and the immune system, often coupled to the expression of a single cytokine transgene. Recently, the importance of TLR activation in mediating adaptive immunity has been demonstrated. We therefore sought to influence the type and level of immune response raised after oncolytic vaccinia therapy through manipulation of TLR signaling. Vaccinia naturally activates TLR2, associated with an antibody response, whereas a CTL response is associated with TLR3-TRIF-signaling pathways. We manipulated TLR signaling by vaccinia through deglycosylation of the viral particle to block TLR2 activation and expression of a TRIF transgene. The resulting vector displayed greatly reduced production of anti-viral neutralizing antibody as well as an increased anti-tumor CTL response. Delivery in both naive and pre-treated mice was enhanced and immunotherapeutic activity dramatically improved.
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Rojas
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Padma
authors.initials: P
authors.lastname: Sampath
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Braulio
authors.initials: B
authors.lastname: Bonilla
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ashley
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Byrd
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: thornesh@upmc.edu.
authors.forename: Steve H
authors.initials: SH
authors.lastname: Thorne
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D006031:Glycosylation; D007167:Immunotherapy; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009336:Necrosis; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D050130:Oncolytic Virotherapy; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014616:Vaccinia virus / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D013937:Thymidine Kinase; D051195:Toll-Like Receptor 2; C476286:Ticam1 protein, mouse