Matrix metalloproteinase 2-mediated immune dysregulation

Extracellular proteinases, such as metalloproteinases (MMPs), are believed to be key players in promoting tumor progression through modulation of the tumor microenvironment. MMP-2 cleaves many components of the extracellular matrix (ECM) and is over-expressed in a large array of cancer types including melanoma. Its activation levels are increased in most malignant cells as compared to normal tissue. High levels of MMP-2 expressed by cancer and/or stromal cells are often associated with later tumor stages, increased dissemination and poorer survival/prognostis. Accordingly, MMP-2 possesses pro-tumoral functions through mechanisms occurring at different levels of tumor progression such as cell growth, invasion/metastasis, angiogenesis and inflammation.

Dr. Godefroy documented the presence of MMP-2-specific CD4+ T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4+ T cells displayed an inflammatory TH2 profile, i.e. mainly secreting TNFα, IL-4 and IL-13 and expressing GATA3. Furthermore, She showed that MMP-2-conditioned human dendritic cells (DCs) primed naïve CD4+ T cells to differentiate into an inflammatory TH2 phenotype through OX40L expression and inhibition of IL-12p70 production:

  • MMP-2 degrades the type-I IFN receptor IFNAR1, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production.
  • Additionally, we recently found that MMP-2 triggers the Toll-like receptor-2 (TLR2), leading to NF-kB activation, OX40L up-regulation on human DCs and ensuing TH2 polarization.

MMP-2-dependent type 2 polarization might represent a key mechanism exploited by the immune system to control a broad array of disorders, such as inflammatory, infectious and autoimmune diseases, which can be hijacked by tumors to evade immunity.

Emmanuelle Godefroy PhD. Assistant Professor

Contact Us

1470 Madison Avenue Room 201
New York, NY 10029 | USA
212-824-8427