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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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TIDCs may express diverse phenotypes but are immature in their majority. (A) DCs were enriched from the indicated solid tumors and analyzed for the expression of CD11c, CD11b, CD8α, and B220 by flow cytometry (log scale). (B) DCs were enriched from peripheral lymph node or from the indicated solid tumors and the expression of MHC class II, CD40, and CD86 molecules was analyzed among gated CD11c+ cells (solid line) compared with isotype control (gray histograms) by flow cytometry (log scale). Data are representative of two to five experiments.
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fig1: TIDCs may express diverse phenotypes but are immature in their majority. (A) DCs were enriched from the indicated solid tumors and analyzed for the expression of CD11c, CD11b, CD8α, and B220 by flow cytometry (log scale). (B) DCs were enriched from peripheral lymph node or from the indicated solid tumors and the expression of MHC class II, CD40, and CD86 molecules was analyzed among gated CD11c+ cells (solid line) compared with isotype control (gray histograms) by flow cytometry (log scale). Data are representative of two to five experiments.

Mentions: We isolated TIDCs from various transplantable tumors as well as from hepatocarcinoma developing in X/myc transgenic mice (13) and analyzed their phenotype (Fig. 1) . TIDCs purified from a subcutaneously implanted C26 colon carcinoma transduced with the 6Ckine chemokine (14) were CD11b+, CD8α−, and B220− in their vast majority (Fig. 1 A). As shown previously, this chemokine-induced model allowed us to recover large numbers of TIDCs, while these were identical to TIDCs isolated from parental C26 tumors. TIDCs isolated from other transplantable tumors had also a similar phenotype, thus resembling the classical myeloid subset of DCs described in the mouse (19). On the other hand, TIDCs isolated from liver hepatocarcinoma were more diverse, including CD11b+ and CD11b− DCs as well as cells expressing CD8α an/or B220, the latter marker being ascribed to mouse type I IFN-producing cells (19, 20). We then compared the expression of MHC class II, CD40, and CD86 molecules of TIDCs to that of lymph node DCs or immature BM-DCs (Figs. 1 B and 2 A). We observed that TIDCs had an immature phenotype, with intermediate levels of surface MHC class II and no detectable CD40 or CD86 molecules, with the exception of the B16 melanoma TIDCs which expressed low levels of CD40 and CD86.


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)

TIDCs may express diverse phenotypes but are immature in their majority. (A) DCs were enriched from the indicated solid tumors and analyzed for the expression of CD11c, CD11b, CD8α, and B220 by flow cytometry (log scale). (B) DCs were enriched from peripheral lymph node or from the indicated solid tumors and the expression of MHC class II, CD40, and CD86 molecules was analyzed among gated CD11c+ cells (solid line) compared with isotype control (gray histograms) by flow cytometry (log scale). Data are representative of two to five experiments.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: TIDCs may express diverse phenotypes but are immature in their majority. (A) DCs were enriched from the indicated solid tumors and analyzed for the expression of CD11c, CD11b, CD8α, and B220 by flow cytometry (log scale). (B) DCs were enriched from peripheral lymph node or from the indicated solid tumors and the expression of MHC class II, CD40, and CD86 molecules was analyzed among gated CD11c+ cells (solid line) compared with isotype control (gray histograms) by flow cytometry (log scale). Data are representative of two to five experiments.
Mentions: We isolated TIDCs from various transplantable tumors as well as from hepatocarcinoma developing in X/myc transgenic mice (13) and analyzed their phenotype (Fig. 1) . TIDCs purified from a subcutaneously implanted C26 colon carcinoma transduced with the 6Ckine chemokine (14) were CD11b+, CD8α−, and B220− in their vast majority (Fig. 1 A). As shown previously, this chemokine-induced model allowed us to recover large numbers of TIDCs, while these were identical to TIDCs isolated from parental C26 tumors. TIDCs isolated from other transplantable tumors had also a similar phenotype, thus resembling the classical myeloid subset of DCs described in the mouse (19). On the other hand, TIDCs isolated from liver hepatocarcinoma were more diverse, including CD11b+ and CD11b− DCs as well as cells expressing CD8α an/or B220, the latter marker being ascribed to mouse type I IFN-producing cells (19, 20). We then compared the expression of MHC class II, CD40, and CD86 molecules of TIDCs to that of lymph node DCs or immature BM-DCs (Figs. 1 B and 2 A). We observed that TIDCs had an immature phenotype, with intermediate levels of surface MHC class II and no detectable CD40 or CD86 molecules, with the exception of the B16 melanoma TIDCs which expressed low levels of CD40 and CD86.

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