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 4

Mmp2 overexpression in B16 cells promotes melanoma tumor growth.

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Mmp2 overexpression in B16 cells promotes melanoma tumor growth. Mmp2 a...
Mmp2 and Mmp9 were OE in B16 F1 cells and injected into mice. (A and B) Tumor kinetics was measured up to 20 days. Tumor volume (A) and weight (B) are displayed. n = 8–10 mice per group. Data are representative of 5 independent experiments with mean ± SEM. *P < 0.05 and **P < 0.01. Two-way ANOVA with Dunnett’s post hoc test. (C) Immunofluorescence (IF) staining for MMP2 (green), CD45 (red), and DAPI (blue). Scale bars: 200 μm. (D–F) CyTOF analysis of lymphoid panel. viSNE plot of immune, stromal, and tumor cell clusters present in the tumors at day 19 (D) identified with aid of single marker expression in all samples. Population comparison between F1 and F1 Mmp-OE tumors (E) were identified, and clusters differentially expressed between the different groups of tumors were identified (F). (G–I) CyTOF analysis of Myeloid panel. viSNE plot of immune, stromal, and tumor cell clusters present in the tumors at day 19 (G) identified with aid of single marker expression in all samples. Population comparison between F1 and F1 MMP-OE tumors (H) were identified, and clusters differentially expressed between the different groups of tumors were identified (I). Data are representative of 2–4 mice with mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001. P values were adjusted using FDR. Statistical analysis was performed using binomial generalized linear mixed-effects model (GLMM). (J) IF of granzyme-B (green) and DAPI (blue) in F1 tumors (top) and F1 Mmp2-OE tumors (bottom). Scale bars: 50 μm. (K) Quantification of GrzB staining. n = 8–12 sections with mean ± SEM. **P < 0.01. Student’s t test.