title: Therapeutic effectiveness of intratumorally delivered dendritic cells engineered to express the pro-inflammatory cytokine, interleukin (IL)-32.
abstract: Interleukin-32 (IL-32) is a pro-inflammatory cytokine conditionally produced by T cells, natural killer (NK) cells, monocytes, epithelial cells and keratinocytes, which has an important role in host resistance against infectious disease. Interestingly, elevated levels of IL-32 transcripts in fine needle aspirates of tumor tissue have also been correlated with objective clinical responses in cancer patients receiving immunotherapy. To evaluate the antitumor impact of IL-32 gene therapy, we treated BALB/c mice bearing established subcutaneous CMS4 sarcomas with intratumoral (i.t.) injections of syngenic dendritic cells (DCs) engineered to express human IL-32β complementary DNA (that is, DC.IL32). Although ectopic expression of IL-32β by DC resulted in only modest phenotypic changes in these antigen-presenting cells, DC.IL32 produced higher levels of IL-12p70 than control DC. DC.IL32 were more potent activators of type-1 T-cell responses in vitro and in vivo, with i.t. administration of DC.IL32 leading to the CD8(+) T-cell-dependent (but CD4(+) T-cell- and NK cell-independent) suppression of tumor growth. Effective DC.IL32-based therapy promoted infiltration of tumors by type-1 (that is, CXCR3(+)VLA-4(+)GrB(+)) CD8(+) T cells and CD11b(+)CD11c(+) host myeloid DC, but led to reductions in the prevalence of CD11b(+)Gr1(+) myeloid-derived suppressor cells and CD31(+) blood vessels.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qu
authors.forename: J L
authors.initials: JL
authors.lastname: Taylor
authors.forename: A
authors.initials: A
authors.lastname: Bose
authors.forename: W J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012509:Sarcoma / Q000628:therapy
chemical_list: D007378:Interleukins; C569037:interleukin-32, mouse