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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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Treatment with CpG 1668 plus anti–IL-10R induces tumor rejection. Groups of seven mice were injected subcutaneously at day 0 with 5 × 104 C26 (A) or B16F0 (B) tumor cells. Mice were treated at day 7, 14, and 21 (arrows) with control antibody, 5 μg CpG 1668 injected intratumorally, 250 μg anti–IL-10R antibody intraperitoneally, or CpG plus anti–IL-10R. Tumor incidence and survival were monitored in all groups for the indicated times.
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fig7: Treatment with CpG 1668 plus anti–IL-10R induces tumor rejection. Groups of seven mice were injected subcutaneously at day 0 with 5 × 104 C26 (A) or B16F0 (B) tumor cells. Mice were treated at day 7, 14, and 21 (arrows) with control antibody, 5 μg CpG 1668 injected intratumorally, 250 μg anti–IL-10R antibody intraperitoneally, or CpG plus anti–IL-10R. Tumor incidence and survival were monitored in all groups for the indicated times.

Mentions: We treated mice implanted with subcutaneous C26 or B16F0 tumors with various combinations of CpG 1668, control GL113 antibody, or anti–IL-10R antibody (Fig. 7, A and B) . We observed that anti–IL-10R or CpG alone had no effect on tumor incidence or survival in the C26 model, nor on tumor incidence in the B16F0 model (Fig. 7, A and B). Treatment with CpG alone had a weak effect on survival in the B16F0 model (Fig. 7 B). In marked contrast, combination of CpG plus anti–IL-10R had a significant effect on tumor incidence (P = 0.01 for C26 and P = 0.05 for B16F0 compared with control by χ2 test) and on survival (P = 0.002 for C26 and P = 0.006 for B16F0 by logrank analysis) in both models (Fig. 7, A and B). We also found similar results in a model where C26–6CK tumors were implanted (unpublished data). Of note, most of the mice treated with CpG plus anti–IL-10R did show palpable tumors, but many developed local necrosis and eventually rejected the tumor.


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)

Treatment with CpG 1668 plus anti–IL-10R induces tumor rejection. Groups of seven mice were injected subcutaneously at day 0 with 5 × 104 C26 (A) or B16F0 (B) tumor cells. Mice were treated at day 7, 14, and 21 (arrows) with control antibody, 5 μg CpG 1668 injected intratumorally, 250 μg anti–IL-10R antibody intraperitoneally, or CpG plus anti–IL-10R. Tumor incidence and survival were monitored in all groups for the indicated times.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Treatment with CpG 1668 plus anti–IL-10R induces tumor rejection. Groups of seven mice were injected subcutaneously at day 0 with 5 × 104 C26 (A) or B16F0 (B) tumor cells. Mice were treated at day 7, 14, and 21 (arrows) with control antibody, 5 μg CpG 1668 injected intratumorally, 250 μg anti–IL-10R antibody intraperitoneally, or CpG plus anti–IL-10R. Tumor incidence and survival were monitored in all groups for the indicated times.
Mentions: We treated mice implanted with subcutaneous C26 or B16F0 tumors with various combinations of CpG 1668, control GL113 antibody, or anti–IL-10R antibody (Fig. 7, A and B) . We observed that anti–IL-10R or CpG alone had no effect on tumor incidence or survival in the C26 model, nor on tumor incidence in the B16F0 model (Fig. 7, A and B). Treatment with CpG alone had a weak effect on survival in the B16F0 model (Fig. 7 B). In marked contrast, combination of CpG plus anti–IL-10R had a significant effect on tumor incidence (P = 0.01 for C26 and P = 0.05 for B16F0 compared with control by χ2 test) and on survival (P = 0.002 for C26 and P = 0.006 for B16F0 by logrank analysis) in both models (Fig. 7, A and B). We also found similar results in a model where C26–6CK tumors were implanted (unpublished data). Of note, most of the mice treated with CpG plus anti–IL-10R did show palpable tumors, but many developed local necrosis and eventually rejected the tumor.

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