The Journal of Experimental Medicine
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Published 19 August 2002. doi:10.1084/jem.20020732
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© Rockefeller University Press, 0022-1007/2002/8/541/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 4, August 19, 2002 541-549

Reversal of Tumor-induced Dendritic Cell Paralysis by CpG Immunostimulatory Oligonucleotide and Anti–Interleukin 10 Receptor Antibody

Alain P. Vicari1, Claudia Chiodoni2, Céline Vaure1, Smina Aït-Yahia1, Christophe Dercamp1, Fabien Matsos1, Olivier Reynard1, Catherine Taverne1, Philippe Merle3, Mario P. Colombo2, Anne O'Garra4, Giorgio Trinchieri1 and Christophe Caux1

1 Schering-Plough Laboratory for Immunological Research, 69571 Dardilly, France
2 Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milano, Italy
3 Institut National de la Sante et de la Recherche Medicale U271, 69424 Lyon, France
4 DNAX Research Institute, Palo Alto, CA 94304

Address correspondence to Alain P. Vicari, Schering-Plough Laboratory for Immunological Research, BP11, 27 chemin des Peupliers, 69571 Dardilly, France. Phone: 33-4-72-17-27-00; Fax: 33-4-78-35-47-50; E-mail: alain.vicari{at}spcorp.com

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.

Key Words: cancer • immunosuppression • immunotherapy • interleukin 12 • Toll-like receptor


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