Effect of matrix metalloproteinase-2 on antitumor immunity.

Abstract

2570 Background: Cancer cells, including melanoma, can be highly resistant to traditional treatments such as chemotherapy and radiotherapy. As a result, a lot of effort has been put into developing immune therapies to treat cancer patients. The main barrier to design effective immunotherapies is the immunosuppression induced by the tumor. Matrix metalloproteinase-2 (MMP-2) is over-expressed in most cancers including melanoma, and its expression is associated with increased dissemination and poorer survival/prognosis. Here, we uncovered an immunosuppressive role of MMP-2 in inducing ineffective/detrimental TH2 immune responses and its underlying mechanisms. Methods: Human dendritic cells (DCs) were cultured in the presence of MMP-2 or various TLR agonists. DCs responses were monitored using immunostaining, ELISA or cytometric bead array methods. Autologous CD4+ T cells were stimulated using these conditioned tumor-associated antigen (TAA)-pulsed DCs. TAA-specific CD4+ T cells were cloned and characterized using the same techniques as for DCs. Results: Herewe showed that MMP-2-conditioned human DCs primed naïve CD4+ T cells into an inflammatory TH2 phenotype, i.e. mainly secreting TNFα, IL-4 and IL-13 and expressing GATA3. Accordingly, we detected MMP-2-specific CD4+ T cells displaying the same inflammatory TH2 profile in tumor-infiltrating lymphocytes from melanoma patients. We revealed the underlying mechanisms: on the one hand, MMP-2 was found to degrade the type-I IFN receptor IFNAR1, thereby preventing STAT1 phosphorylation, which is necessary for IL-12 production. On the other hand, MMP-2 triggers the Toll-like receptor (TLR)-2 on DCs, which leads to NF-kB activation and OX40L expression. Both lack of IL-12 and over-expression of OX40L were found responsible for skewing T cell responses towards a detrimental TH2 phenotype. Conclusions: MMP-2, therefore, acts as an endogenous TH2 "conditioner" and may underlie the prevalence of detrimental TH2 responses in cancer. Our findings also described the responsible MMP-2-dependent mechanisms, which open the way to novel therapeutic strategies and/or targets to skew anti-tumor CD4+ T cell responses towards a more efficient anti-tumor TH1 phenotype to treat cancer patients.