TY - JOUR
T1 - MMP2 and TLRs modulate immune responses in the tumor microenvironment
AU - Muniz-Bongers, Luciana R.
AU - McClain, Christopher B.
AU - Saxena, Mansi
AU - Bongers, Gerold
AU - Merad, Miriam
AU - Bhardwaj, Nina
N1 - Publisher Copyright:
© 2021, Muniz-Bongers et al.
PY - 2021/6/22
Y1 - 2021/6/22
N2 - 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. We found that MMP2 signals proinflammatory pathways on antigen presenting cells, and this requires both TLR2 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 intratumoral 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 DC-T cell cross-talk as they are lost in Batf3-/- and Rag2-/- mice. These findings provide insights into the detrimental role of endogenous alarmins like MMP2 in modulating immune responses in the tumor microenvironment.
AB - 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. We found that MMP2 signals proinflammatory pathways on antigen presenting cells, and this requires both TLR2 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 intratumoral 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 DC-T cell cross-talk as they are lost in Batf3-/- and Rag2-/- mice. These findings provide insights into the detrimental role of endogenous alarmins like MMP2 in modulating immune responses in the tumor microenvironment.
UR - http://www.scopus.com/inward/record.url?scp=85108406214&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.144913
DO - 10.1172/jci.insight.144913
M3 - Article
C2 - 34032639
AN - SCOPUS:85108406214
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 12
M1 - e144913
ER -