TLR4 Engagement During TLR3-induced Proinflammatory Signaling in Dendritic Cells Promotes IL-10-mediated Suppression of Antitumor Immunity

Overview

Journal Cancer Res

Specialty Oncology

Date 2011 Jul 7

PMID 21730023

Citations 28

Authors

Dusan Bogunovic

Olivier Manches

Emmanuelle Godefroy

Alice Yewdall

Anne Gallois

Andres M Salazar

Isabelle Marie

David E Levy

Nina Bhardwaj

Affiliations

Soon will be listed here.

Abstract

Toll-like receptor (TLR) agonists are promising adjuvants for immune therapy of cancer, but their potential efficacy as single or combinatorial agents has yet to be fully evaluated. Here, we report that among all TLR agonists tested, dendritic cells (DC) stimulated with the TLR3 agonist polyI:C displayed the strongest activity in stimulating proinflammatory responses and the production of melanoma antigen-specific CD8(+) T cells. Simultaneous treatment with TLR7/8 agonists further improved these responses, but the inclusion of bacterial lipopolysaccharide (LPS), a TLR4 agonist, suppressed proinflammatory cytokine production. This inhibition was contingent upon rapid induction of the suppressive cytokine interleukin (IL)-10 by LPS, leading to dysregulated immune responses and it could be reversed by signal transducers and activators of transcription 3 knockdown, p38 blockade or antibodies to IL-10 and its receptor. Our findings show how certain TLR agonist combinations can enhance or limit DC responses associated with antitumor immunity, through their relative ability to induce IL-10 pathways that are immune suppressive.

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