Upregulation of natural killer cells functions underlies the efficacy of intratumorally injected dendritic cells engineered to produce interleukin-12

Rodríguez‐Calvillo, Mercedes; Duarte, Marina; Tirapu, Iñigo; Berraondo, Pedro; Mazzolini, Guillermo; Qian, Chen; Prìeto, Jesús; Melero, Ignacio

doi:10.1016/s0301-472x(01)00792-5

Cited by 26 publications

(27 citation statements)

References 50 publications

(70 reference statements)

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“…DCs labeled with the GFP gene or fluorochromes reach the interfollicular areas of lymph nodes quite efficiently. 13,27,31 Preclinical efficacy in rodents prompted clinical development of intratumoral injection of DCs that had been engineered to produce IL-12. In our studies in human patients harboring digestive carcinomas, deficient migration seems to be an important issue.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells delivered inside human carcinomas are sequestered by interleukin‐8

Feijoó

Alfaro

Mazzolini

et al. 2005

Intl Journal of Cancer

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In the course of a clinical trial consisting of intratumoral injections of dendritic cells (DCs) transfected to produce interleukin-12, the use of In-labeled tracing doses of DCs showed that most DCs remained inside tumor tissue, instead of migrating out. In search for factors that could explain this retention, it was found that tumors from patients suffering hepatocellular carcinoma, colorectal or pancreatic cancer were producing IL-8 and that this chemokine attracted monocyte-derived dendritic cells that uniformly express both IL-8 receptors CXCR1 and CXCR2. Accordingly, neutralizing antihuman IL-8 monoclonal antibodies blocked the chemotactic attraction of DCs by recombinant IL-8, as well as by the serum of the patients or culture supernatants of human colorectal carcinomas. In addition, tissue culture supernatants of colon carcinoma cells inhibited DC migration induced by MIP-3b in an IL-8-dependent fashion. IL-8 production in malignant tissue and the responsiveness of DCs to IL-8 are a likely explanation of the clinical images, which suggest retention of DCs inside human malignant lesions. Impairment of DC migration toward lymphoid tissue could be involved in cancer immune evasion. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Dendritic cells delivered inside human carcinomas are sequestered by interleukin‐8

Feijoó

Alfaro

Mazzolini

et al. 2005

Intl Journal of Cancer

Self Cite

111

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“…In particular, IL-12 favours differentiation of Th1 helper cells and activates NK cells, providing a link between the innate and adaptive immune response. 17 DC transfected to secrete high levels of IL-12 have been used successfully in a range of antitumour strategies, [18][19][20] supporting a role for local DC-derived IL-12 in tumour immunotherapy.…”

Section: Fusogenic Membrane Glycoprotein-mediated Immune Priming F Ermentioning

confidence: 99%

Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming

et al. 2005

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Fusogenic membrane glycoproteins (FMG) are a family of viral genes that, when expressed in tumour cells, trigger extensive cell to cell fusion and subsequent cell death. Gene therapy approaches using FMG are also potentially immunogenic, since syncitia generated ex vivo can be therapeutic as antitumour vaccines in murine models. This study has addressed the mechanisms responsible for the immunogenicity of FMG-mediated cell death, and its applicability to human immune priming. We show that fusion of human Mel888 melanoma cells following transfection with FMG can reverse the suppressive effects of Mel888 on dendritic cells (DC) phenotype, and potentiate IL-12 production by DC on activation in a cell contact-dependent manner. DC loaded with fusing, but not intact, tumour cells primed a naive, tumour-specific cytotoxic T-cell response, which was MHC class I-restricted and associated with production of high levels of IFNg and, later, IL-5. Fusing cells were an effective source of antigen for DC cross-priming and presentation of the melanoma-specific antigen gp100 to a specific T-cell clone. These data show, in a human system, that FMG represent an immunogenic, as well as cytotoxic, gene therapy for cancer, reversing the inhibitory effects of tumour cells on DC to potentiate IL-12 production and naive T-cell priming.

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“…In the context of intratumor injection, it is interesting that DC can mediate a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent killing of tumor cells, thus creating apoptotic bodies available for uptake by the killer DC [134]. Cytotoxicity as mediated by natural killer cells, CTLs, or macrophages could have similar consequences in terms of generating antigenic material for crosspresentation [135]. …”

Section: Intratumor Injection Of DCmentioning

confidence: 99%

Clinical implications of antigen transfer mechanisms from malignant to dendritic cells

Arina

Tirapu

Alfaro

et al. 2002

Experimental Hematology

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Upregulation of natural killer cells functions underlies the efficacy of intratumorally injected dendritic cells engineered to produce interleukin-12

Cited by 26 publications

References 50 publications

Dendritic cells delivered inside human carcinomas are sequestered by interleukin‐8

Dendritic cells delivered inside human carcinomas are sequestered by interleukin‐8

Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming

Clinical implications of antigen transfer mechanisms from malignant to dendritic cells

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