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
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