Limits...
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.

Show MeSH

Related in: MedlinePlus

Treatment with CpG 1668 plus anti–IL-10R induces T cell and NK cell–mediated tumor rejection as well as antitumor immune memory. Groups of seven mice were injected subcutaneously at day 0 with 5 × 104 C26 tumor cells. (A) Mice were treated at day 7, 14, and 21 (arrows) with control or 5 μg CpG 1668 injected intratumorally plus 250 μg anti–IL-10R antibody intraperitoneally. Indicated groups of mice receiving anti–IL-10R plus CpG were further treated with anti-CD4, anti-CD8, or Asialo-GM1 depleting antibodies as described in Materials and Methods. (B) Immunodeficient SCID mice were treated at day 7, 14, and 21 (arrows) with control, 5 μg CpG 1668 injected intratumorally, 250 μg anti–IL-10R antibody intraperitoneally or CpG plus anti–IL-10R. (C) Mice were injected intratumorally at day 7, 14, and 21 (arrows) with 5 × 104 enriched tumor-infiltrating DCs activated for 2 h in vitro with none, LPS plus anti-CD40 plus anti–IL-10R, or CpG plus anti–IL-10R, as well as intraperitoneally with 250 μg anti–IL-10R antibody. (D) Mice treated with CpG plus anti–IL-10R that had rejected a C26 tumor inoculated at day 0 (n = 12) were rechallenged at day 45 with 5 × 104 C26 cells in the contralateral flank and compared naive mice challenged with the same inoculum. Tumor incidence and survival were monitored in all groups for the indicated times.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2196048&req=5

fig8: Treatment with CpG 1668 plus anti–IL-10R induces T cell and NK cell–mediated tumor rejection as well as antitumor immune memory. Groups of seven mice were injected subcutaneously at day 0 with 5 × 104 C26 tumor cells. (A) Mice were treated at day 7, 14, and 21 (arrows) with control or 5 μg CpG 1668 injected intratumorally plus 250 μg anti–IL-10R antibody intraperitoneally. Indicated groups of mice receiving anti–IL-10R plus CpG were further treated with anti-CD4, anti-CD8, or Asialo-GM1 depleting antibodies as described in Materials and Methods. (B) Immunodeficient SCID mice were treated at day 7, 14, and 21 (arrows) with control, 5 μg CpG 1668 injected intratumorally, 250 μg anti–IL-10R antibody intraperitoneally or CpG plus anti–IL-10R. (C) Mice were injected intratumorally at day 7, 14, and 21 (arrows) with 5 × 104 enriched tumor-infiltrating DCs activated for 2 h in vitro with none, LPS plus anti-CD40 plus anti–IL-10R, or CpG plus anti–IL-10R, as well as intraperitoneally with 250 μg anti–IL-10R antibody. (D) Mice treated with CpG plus anti–IL-10R that had rejected a C26 tumor inoculated at day 0 (n = 12) were rechallenged at day 45 with 5 × 104 C26 cells in the contralateral flank and compared naive mice challenged with the same inoculum. Tumor incidence and survival were monitored in all groups for the indicated times.

Mentions: In several additional groups of C26 tumor-bearing mice inoculated with C26 tumor cells and treated with anti–IL-10R plus CpG, we injected antibodies in order to deplete CD4+ or CD8+ cells or NK cell activity (Fig. 8 A). Although CpG plus anti–IL-10R antibody induced some level of tumor rejection in depleted groups, the combination was less efficient than in nondepleted groups. All mice which rejected the tumor remain tumor-free for the rest of the experiments while those which developed tumors were killed between 4 to 6 wk for antibody-depleted groups and 3 to 5 wk for SCID mice. These data suggest that several components of the adaptive and innate immune response, including CD4+, CD8+ T cells, and NK cells, might contribute to tumor eradication. We also treated C26 tumor-bearing SCID mice, which lack T and B cells (Fig. 8 B). There was no significant impact of the treatment on tumor incidence and survival, strongly suggesting a role for T cell and perhaps B cells in the therapeutic effect of CpG plus anti–IL-10R in immunocompetent mice.


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 T cell and NK cell–mediated tumor rejection as well as antitumor immune memory. Groups of seven mice were injected subcutaneously at day 0 with 5 × 104 C26 tumor cells. (A) Mice were treated at day 7, 14, and 21 (arrows) with control or 5 μg CpG 1668 injected intratumorally plus 250 μg anti–IL-10R antibody intraperitoneally. Indicated groups of mice receiving anti–IL-10R plus CpG were further treated with anti-CD4, anti-CD8, or Asialo-GM1 depleting antibodies as described in Materials and Methods. (B) Immunodeficient SCID mice were treated at day 7, 14, and 21 (arrows) with control, 5 μg CpG 1668 injected intratumorally, 250 μg anti–IL-10R antibody intraperitoneally or CpG plus anti–IL-10R. (C) Mice were injected intratumorally at day 7, 14, and 21 (arrows) with 5 × 104 enriched tumor-infiltrating DCs activated for 2 h in vitro with none, LPS plus anti-CD40 plus anti–IL-10R, or CpG plus anti–IL-10R, as well as intraperitoneally with 250 μg anti–IL-10R antibody. (D) Mice treated with CpG plus anti–IL-10R that had rejected a C26 tumor inoculated at day 0 (n = 12) were rechallenged at day 45 with 5 × 104 C26 cells in the contralateral flank and compared naive mice challenged with the same inoculum. 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

fig8: Treatment with CpG 1668 plus anti–IL-10R induces T cell and NK cell–mediated tumor rejection as well as antitumor immune memory. Groups of seven mice were injected subcutaneously at day 0 with 5 × 104 C26 tumor cells. (A) Mice were treated at day 7, 14, and 21 (arrows) with control or 5 μg CpG 1668 injected intratumorally plus 250 μg anti–IL-10R antibody intraperitoneally. Indicated groups of mice receiving anti–IL-10R plus CpG were further treated with anti-CD4, anti-CD8, or Asialo-GM1 depleting antibodies as described in Materials and Methods. (B) Immunodeficient SCID mice were treated at day 7, 14, and 21 (arrows) with control, 5 μg CpG 1668 injected intratumorally, 250 μg anti–IL-10R antibody intraperitoneally or CpG plus anti–IL-10R. (C) Mice were injected intratumorally at day 7, 14, and 21 (arrows) with 5 × 104 enriched tumor-infiltrating DCs activated for 2 h in vitro with none, LPS plus anti-CD40 plus anti–IL-10R, or CpG plus anti–IL-10R, as well as intraperitoneally with 250 μg anti–IL-10R antibody. (D) Mice treated with CpG plus anti–IL-10R that had rejected a C26 tumor inoculated at day 0 (n = 12) were rechallenged at day 45 with 5 × 104 C26 cells in the contralateral flank and compared naive mice challenged with the same inoculum. Tumor incidence and survival were monitored in all groups for the indicated times.
Mentions: In several additional groups of C26 tumor-bearing mice inoculated with C26 tumor cells and treated with anti–IL-10R plus CpG, we injected antibodies in order to deplete CD4+ or CD8+ cells or NK cell activity (Fig. 8 A). Although CpG plus anti–IL-10R antibody induced some level of tumor rejection in depleted groups, the combination was less efficient than in nondepleted groups. All mice which rejected the tumor remain tumor-free for the rest of the experiments while those which developed tumors were killed between 4 to 6 wk for antibody-depleted groups and 3 to 5 wk for SCID mice. These data suggest that several components of the adaptive and innate immune response, including CD4+, CD8+ T cells, and NK cells, might contribute to tumor eradication. We also treated C26 tumor-bearing SCID mice, which lack T and B cells (Fig. 8 B). There was no significant impact of the treatment on tumor incidence and survival, strongly suggesting a role for T cell and perhaps B cells in the therapeutic effect of CpG plus anti–IL-10R in immunocompetent mice.

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