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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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DCs from various transplantable or transgene-induced tumors are refractory to activation with LPS, IFN-γ plus anti-CD40 but not with CpG 1668 plus anti–IL-10R. The ability of TIDC populations enriched from the indicated tumors to produce IL-12 in response to LPS plus IFN-γ and anti-CD40 or CpG 1668 plus anti–IL-10R was analyzed: (A) by intracellular staining for IL-12p40/p70 together with surface CD11c staining (log scale), percentages of CD11c+ cells expressing intracellular IL-12 are indicated in the top right quadrant; (B) by measuring IL-12 p70 levels in TIDC culture supernatant by ELISA. Results (log scale) are expressed as the mean concentration ± SEM from triplicate cultures.
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fig6: DCs from various transplantable or transgene-induced tumors are refractory to activation with LPS, IFN-γ plus anti-CD40 but not with CpG 1668 plus anti–IL-10R. The ability of TIDC populations enriched from the indicated tumors to produce IL-12 in response to LPS plus IFN-γ and anti-CD40 or CpG 1668 plus anti–IL-10R was analyzed: (A) by intracellular staining for IL-12p40/p70 together with surface CD11c staining (log scale), percentages of CD11c+ cells expressing intracellular IL-12 are indicated in the top right quadrant; (B) by measuring IL-12 p70 levels in TIDC culture supernatant by ELISA. Results (log scale) are expressed as the mean concentration ± SEM from triplicate cultures.

Mentions: We analyzed CD11c and IL-12 p40/p70 intracellular expression after overnight activation with either LPS plus IFN-γ plus anti-CD40 or CpG plus anti–IL-10R in TIDCs enriched from C26, B16F0, LL2, and TSA transplantable tumors as well as from X/myc hepatocarcinoma (Fig. 6 A). As for C26–6CK TIDCs, DCs isolated from these tumors did not respond to LPS plus IFN-γ plus anti-CD40 but showed a robust response to CpG plus anti–IL-10R (Fig. 6 A). Identical results were obtained by measuring IL-12p70 levels in culture supernatants, albeit we detected minimal IL-12p70 secretion by B16F0 melanoma TIDCs activated with LPS plus IFN-γ plus anti-CD40 (Fig. 6 B). Thus, the refractory state of TIDCs to LPS plus IFN-γ plus anti-CD40 activation and their sensitivity to CpG plus anti–IL-10R can be observed in tumors from different histological origin as well as in a transgenic tumor model.


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)

DCs from various transplantable or transgene-induced tumors are refractory to activation with LPS, IFN-γ plus anti-CD40 but not with CpG 1668 plus anti–IL-10R. The ability of TIDC populations enriched from the indicated tumors to produce IL-12 in response to LPS plus IFN-γ and anti-CD40 or CpG 1668 plus anti–IL-10R was analyzed: (A) by intracellular staining for IL-12p40/p70 together with surface CD11c staining (log scale), percentages of CD11c+ cells expressing intracellular IL-12 are indicated in the top right quadrant; (B) by measuring IL-12 p70 levels in TIDC culture supernatant by ELISA. Results (log scale) are expressed as the mean concentration ± SEM from triplicate cultures.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: DCs from various transplantable or transgene-induced tumors are refractory to activation with LPS, IFN-γ plus anti-CD40 but not with CpG 1668 plus anti–IL-10R. The ability of TIDC populations enriched from the indicated tumors to produce IL-12 in response to LPS plus IFN-γ and anti-CD40 or CpG 1668 plus anti–IL-10R was analyzed: (A) by intracellular staining for IL-12p40/p70 together with surface CD11c staining (log scale), percentages of CD11c+ cells expressing intracellular IL-12 are indicated in the top right quadrant; (B) by measuring IL-12 p70 levels in TIDC culture supernatant by ELISA. Results (log scale) are expressed as the mean concentration ± SEM from triplicate cultures.
Mentions: We analyzed CD11c and IL-12 p40/p70 intracellular expression after overnight activation with either LPS plus IFN-γ plus anti-CD40 or CpG plus anti–IL-10R in TIDCs enriched from C26, B16F0, LL2, and TSA transplantable tumors as well as from X/myc hepatocarcinoma (Fig. 6 A). As for C26–6CK TIDCs, DCs isolated from these tumors did not respond to LPS plus IFN-γ plus anti-CD40 but showed a robust response to CpG plus anti–IL-10R (Fig. 6 A). Identical results were obtained by measuring IL-12p70 levels in culture supernatants, albeit we detected minimal IL-12p70 secretion by B16F0 melanoma TIDCs activated with LPS plus IFN-γ plus anti-CD40 (Fig. 6 B). Thus, the refractory state of TIDCs to LPS plus IFN-γ plus anti-CD40 activation and their sensitivity to CpG plus anti–IL-10R can be observed in tumors from different histological origin as well as in a transgenic tumor model.

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