Skip to content

Advertisement

  • Oral presentation
  • Open Access

Activation of Toll-like receptor-2 by tumor associated matrix metalloproteinase-2 modulates dendritic cell function

  • Emmanuelle Godefroy1 and
  • Nina Bhardwaj2
Journal for ImmunoTherapy of Cancer20142(Suppl 3):O21

https://doi.org/10.1186/2051-1426-2-S3-O21

Published: 6 November 2014

Keywords

Human Dendritic CellOX40L ExpressionDendritic Cell FunctionInnate Immune FunctionModulate Cell Proliferation

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which degrade extracellular matrix proteins and modulate cell proliferation, migration, differentiation and angiogenesis. MMP-2, a member of the gelatinase subfamily of MMPs, participates in the remodeling and resolution of tissue injury and tumorigenesis. We recently identified an unexpected new role for MMP-2 in the modulation of innate immune function and in the differentiation of inflammatory TH2 responses in the tumor microenvironment [1]. Pre-exposure to MMP-2 inhibits IL-12 function and up-regulates OX40L expression by human dendritic cells (DCs). Enzymatically active MMP-2 causes degradation of the IFNAR1 chain of the type-I IFN receptor, reducing the ability of IFN beta to enhance transcription of the IL-12p35 subunit through STAT1 phosphorylation. In the absence of IL-12, OX40L now functions as a key co-stimulatory molecule for the priming of TH2 cells. Indeed, we have identified TH2 cells within the TIL compartment of melanoma specimens that produce IL-4, TNF and IL-13. However, the TH2 mechanism by which MMP-2 up-regulates OX40L is not known and the role of MMP-2-driven TH2 cells in vivo has not been determined. In this study, we specifically investigated how MMP-2 up-regulates OX40L on DCs to drive type-2 polarization and the physiologic role of MMP-2 imprinted DC in driving TH2 cells. We identified a novel physiological receptor, namely TLR2, for MMP-2 on DCs that, upon activation, up regulates OX40L and induces the production of TNF and IL-6. Significantly, MMP-2 acted as an adjuvant to prime TH2 cells in vivo towards protein antigens. Therefore, extracellular MMP-2 including that derived from tumors has the potential to locally affect DCs leading to modulation of immune responses in malignant diseases.

Authors’ Affiliations

(1)
New York Blood Center LFKRI, New York, USA
(2)
Icahn School of Medicine at Mt Sinai, NY, USA

References

  1. Godefroy E, Manches O, Dreno B, Hochman T, Rolnitzky L, Labarriere N, Guilloux Y, Goldberg J, Jotereau F, Bhardwaj N: Matrix Metalloproteinase-2 Conditions Human Dendritic Cells to Prime Inflammatory T(H)2 Cells via an IL-12- and OX40L-Dependent Pathway. Cancer Cell. 2011, 19: 333-346. 10.1016/j.ccr.2011.01.037.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Godefroy and Bhardwaj; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement