MMP2 and TLRs modulate immune responses in the tumor microenvironment
Luciana R. Muniz-Bongers, Christopher B. McClain, Mansi Saxena, Gerold Bongers, Miriam Merad, Nina Bhardwaj
Luciana R. Muniz-Bongers, Christopher B. McClain, Mansi Saxena, Gerold Bongers, Miriam Merad, Nina Bhardwaj
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Research Article Immunology Oncology

MMP2 and TLRs modulate immune responses in the tumor microenvironment

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. 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.

Authors

Luciana R. Muniz-Bongers, Christopher B. McClain, Mansi Saxena, Gerold Bongers, Miriam Merad, Nina Bhardwaj

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Figure 1

MMP2 signaling is mediated by TLR2 and TLR4.

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MMP2 signaling is mediated by TLR2 and TLR4. Proinflammatory cytokine se...
Proinflammatory cytokine secretion by primary APCs and immortalized APC cell lines. Briefly, cells were stimulated with MMP2, MMP9, vehicle control, or TLR agonists overnight. All stimulations were performed with 2 × 105 cells per condition in 200 μL volume. Sixteen to 18 hours after stimulation, supernatants were collected and cytometric bead array (CBA) for mouse inflammatory cytokines was performed. (A and B) BMDMs (A) and BMDCs (B) responded to stimulation and secreted TNF-α and IL-6. n = 2. Data are representative of 2 independent experiments with mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001. One-way ANOVA with Dunnett’s post hoc test. (C) TNF-α secretion by Im-MACS from WT and Tlr-deficient mice. Each graph represents the ratio over unstimulated cells. n = 2–4. Data are representative of 4 independent experiments with mean ± SEM. *P < 0.05. One-way ANOVA with Dunnett’s post hoc test. (D and E) TNF-α and IL-6 secretion by primary CD11c+ DCs isolated from lung (D) and spleen (E). n = 2. Data representative of 2 experiments. Mean ± SEM. *P < 0.05 and **P < 0.01 versus Tlr2–/– Tlr4–/– cells. Multiple unpaired t test with using Holm-Sidak correction for multiple comparisons. (F) TNF-α secretion in serum of WT, Tlr2–/–, Tlr4–/–, and Tlr2–/– Tlr4–/– mice 3 hours after i.v. injection with Vehicle, MMP2, Pam3CSK4, and LPS. Data are representative of 4 independent experiments with mean ± SEM. **P < 0.01. Two-way ANOVA with Dunnett’s post hoc test.