The presence of an immunosuppressive tumor microenvironment is a major obstacle in the success of cancer immunotherapies. Because extracellular matrix components can shape the microenvironment, we investigated the role of matrix metalloproteinase 2 (MMP2) in melanoma tumorigenesis. Significantly, we found that MMP2 signals pro-inflammatory pathways on antigen presenting cells which requires both toll-like receptor (TLR) 2 and TLR4. B16 melanoma cells that express MMP2 at baseline have slower kinetics in Tlr2-/-Tlr4-/- mice, implicating MMP2 in promoting tumor growth. Indeed, Mmp2 overexpression in B16 cells potentiated rapid tumor growth which was accompanied by reduced intra-tumoral cytolytic cells and increased M2 macrophages. In contrast, knockdown of Mmp2 slowed tumor growth, and enhanced T cell proliferation and NK cell recruitment. Finally we found that these effects of MMP2 are mediated through dysfunctional dendritic cell (DC) - T cell cross-talk as they are lost in Batf3-/- and Rag2-/- mice, respectively. These findings provide insights into the detrimental role of endogenous alarmins like MMP2 in modulating immune responses in the tumor microenvironment.
Luciana R. Muniz-Bongers, Christopher B. McClain, Mansi Saxena, Gerold Bongers, Miriam Merad, Nina Bhardwaj