title: Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity.
abstract: Dendritic cells (DCs) were adenovirally engineered to constitutively and durably secrete the potent Th1-biasing cytokines interleukin (IL)-12 (AdIL12DC) and/or IL-18 (AdIL18DC) and evaluated for their ability to promote therapeutic antitumor immunity in murine sarcoma models. Injection of either AdIL12DC or AdIL18DC into day 7 CMS4 or MethA tumors resulted in tumor rejection or slowed tumor growth when compared with control cohorts. Importantly, intratumoral injection with DCs engineered to secrete both IL-12 and IL-18 (AdIL12/IL18DC) resulted in complete and the most acute rejection of any treatment group analyzed. This strategy was also effective in promoting the regression of contralateral, untreated tumors. Both CD4+ and CD8+ T cells were required for tumor rejection. CD8+ splenic T cells from mice treated with AdIL12/IL18DC produced the highest levels of IFN-gamma in response to tumor rechallenge in vitro and displayed the broadest repertoire of Tc1-type reactivity to acid-eluted, tumor-derived peptides among all treatment cohorts. This apparent enhancement in cross-presentation of tumor-associated epitopes in vivo may result from the increased capacity of engineered DCs to kill tumor cells, survive tumor-induced apoptosis, and present immunogenic MHC/tumor peptide complexes to T cells after intratumoral injection. In support of this hypothesis, cytokine gene-engineered DCs expressed higher levels of MHC and costimulatory molecules, as well as Fas ligand and membrane-bound tumor necrosis factor alpha, with the latter markers associated with elevated tumoricidal activity in vitro. Cytokine gene-engineered DCs appeared to have a survival advantage in situ when injected into tumor lesions, to be found in approximation with regions of tumor apoptosis, and to have the capacity to ingest apoptotic tumor bodies. These results support the ability of combined cytokine gene transfer to enhance multiple effector functions mediated by intralesionally injected DCs that may concertedly promote cross-priming and the accelerated immune-mediated rejection of tumors.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, The Hillman Cancer Center, 5117 Center Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
authors.forename: Andrea
authors.initials: A
authors.lastname: Gambotto
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.forename: Nikola L
authors.initials: NL
authors.lastname: Vujanovic
authors.forename: Sean M
authors.initials: SM
authors.lastname: Alber
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000502:physiology / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D051017:Apoptosis Regulatory Proteins; D018984:Epitopes, T-Lymphocyte; D020382:Interleukin-18; D008233:Lymphotoxin-alpha; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12