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Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody.

Vicari AP, Chiodoni C, Vaure C, Aït-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O'Garra A, Trinchieri G, Caux C - J. Exp. Med. (2002)

Bottom Line: Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs.In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production.Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.

View Article: PubMed Central - PubMed

Affiliation: Schering-Plough Laboratory for Immunological Research, BP11, 27 chemin des Peupliers, 69571 Dardilly, France. alain.vicari@spcorp.com

ABSTRACT
Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.

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Related in: MedlinePlus

CpG 1668 plus anti–IL-10R activates tumor-infiltrating DCs in vivo. Mice bearing C26–6CK tumors were injected intratumorally with 5 μg CpG 1668 or control GpG sequence and/or intraperitoneally with 250 μg anti–IL-10R or isotype control antibody. 2 h after injection, mice were killed, and TIDCs enriched and stained for intracellular IL-12 p40/p70 and surface CD11c. The percentage of IL-12–positive cells among CD11c-enriched TIDCs was determined by comparison with isotype control and is indicated in the top right corner.
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fig4: CpG 1668 plus anti–IL-10R activates tumor-infiltrating DCs in vivo. Mice bearing C26–6CK tumors were injected intratumorally with 5 μg CpG 1668 or control GpG sequence and/or intraperitoneally with 250 μg anti–IL-10R or isotype control antibody. 2 h after injection, mice were killed, and TIDCs enriched and stained for intracellular IL-12 p40/p70 and surface CD11c. The percentage of IL-12–positive cells among CD11c-enriched TIDCs was determined by comparison with isotype control and is indicated in the top right corner.

Mentions: We injected C26–6CK tumor-bearing mice with CpG intratumorally and/or with anti–IL-10R antibody intraperitoneally in an attempt to activate TIDCs in vivo (Fig. 4) . We observed that CpG plus anti-IL-10R induced the secretion of intracellular IL-12 p40/70 in a large proportion of TIDCs as soon as 2 h after treatment, whereas CpG had a minimal effect and anti–IL-10R alone had no effect.


Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody.

Vicari AP, Chiodoni C, Vaure C, Aït-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O'Garra A, Trinchieri G, Caux C - J. Exp. Med. (2002)

CpG 1668 plus anti–IL-10R activates tumor-infiltrating DCs in vivo. Mice bearing C26–6CK tumors were injected intratumorally with 5 μg CpG 1668 or control GpG sequence and/or intraperitoneally with 250 μg anti–IL-10R or isotype control antibody. 2 h after injection, mice were killed, and TIDCs enriched and stained for intracellular IL-12 p40/p70 and surface CD11c. The percentage of IL-12–positive cells among CD11c-enriched TIDCs was determined by comparison with isotype control and is indicated in the top right corner.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196048&req=5

fig4: CpG 1668 plus anti–IL-10R activates tumor-infiltrating DCs in vivo. Mice bearing C26–6CK tumors were injected intratumorally with 5 μg CpG 1668 or control GpG sequence and/or intraperitoneally with 250 μg anti–IL-10R or isotype control antibody. 2 h after injection, mice were killed, and TIDCs enriched and stained for intracellular IL-12 p40/p70 and surface CD11c. The percentage of IL-12–positive cells among CD11c-enriched TIDCs was determined by comparison with isotype control and is indicated in the top right corner.
Mentions: We injected C26–6CK tumor-bearing mice with CpG intratumorally and/or with anti–IL-10R antibody intraperitoneally in an attempt to activate TIDCs in vivo (Fig. 4) . We observed that CpG plus anti-IL-10R induced the secretion of intracellular IL-12 p40/70 in a large proportion of TIDCs as soon as 2 h after treatment, whereas CpG had a minimal effect and anti–IL-10R alone had no effect.

Bottom Line: Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs.In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production.Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.

View Article: PubMed Central - PubMed

Affiliation: Schering-Plough Laboratory for Immunological Research, BP11, 27 chemin des Peupliers, 69571 Dardilly, France. alain.vicari@spcorp.com

ABSTRACT
Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.

Show MeSH
Related in: MedlinePlus