Muniz-Bongers et al. used murine melanoma models to dissect the immunoregulatory role of MMP2 in the TME. MMP2 stimulated inflammatory cytokines in murine APCs in vitro, dependent on both TLR2 and TLR4. Overexpression of Mmp2 in B16 melanoma cells accelerated tumor growth in vivo, accompanied by decreased CD8+ T cells and cross-presenting CD103+ DCs, and increased M2-like macrophages in the TME. Enhanced tumor growth was abrogated in TLR2/4 double knockout hosts. Conversely, depletion of Mmp2 in B16 cells decreased tumor growth, which correlated with greater numbers of CD8+ T cells, NK cells, CD103+ DCs and M1-like macrophages.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America. (2) The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Author Info: (1) The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America. (2) The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America. (3) The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America. (4) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America. (5) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America. (6) The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America.
