Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and over-expressed by many tumors. Here, we 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 GATA-3. Furthermore, MMP-2-conditioned 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, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type-2 “conditioner” and may play a role in the observed prevalence of detrimental type-2 responses in melanoma.
Several melanoma-associated antigens have been targeted in immunization strategies to treat melanoma patients. However, the therapeutic efficacy of these approaches remains limited, indicating an urgent need for improvement. Because MMP-2 activity is critical for melanoma progression, it represents an interesting target for vaccine therapy. We show that MMP-2 is an immunogenic tumor antigen. However, MMP-2-specific CD4+ T lymphocytes display a suboptimal inflammatory TH2 profile. MMP-2-conditoned DCs prime TH2 responses against several melanoma-associated antigen (MAA), suggesting that MMP-2 can create a TH2 skewing microenvironment in a bystander fashion. Elucidation of the underlying mechanisms opens the way to improving immune responses towards a more effective TH1 response, and highlights the potential of MMP2 as a target antigen in melanoma.