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 6

MMP2 signaling in B16 TME involves BATF3 DCs and lymphoid cells.

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MMP2 signaling in B16 TME involves BATF3 DCs and lymphoid cells. The rol...
The roles of lymphoid cells and BATF3 DCs were evaluated by using Rag2–/–and Batf3–/– mice, respectively. Mice were s.c. injected with 3 × 105 B16 F1, F1 Mmp2-OE, Mmp9-OE, or F1 Mmp2-KO cells, and tumors were measured up to 20 days. (A–D) Tumor growth comparison in Batf3–/– mice. Tumor volume (A) and weight (B) are displayed. Data are representative of 3 experiments with mean ± SEM and 8–10 mice per group. One-way ANOVA with Dunnett’s post hoc test. FACS analysis on day 18 shows changes in hematopoietic cell infiltration for lymphoid (C) and myeloid cells (D). Data are representative of 2 experiments with mean ± SEM and 4 mice per group. Two-way ANOVA with Dunnett’s post hoc test. (E and F) Tumor growth comparison in Rag2–/– mice. Tumor volume (E) and weight (F) are displayed. (G) FACS analysis on day 18 shows changes in hematopoietic cell infiltration. Data are representative of 2 experiments with mean ± SEM and 5–7 mice per group. (H and I) Tumor growth comparison in Rag2–/– mice transferred with OTII cells and B16 OVA-OE tumors. Tumor volume (H) and survival curve (I) are displayed. (J) FACS analysis of ex vivo stimulated CD4+ T cells from tumors at day 18. Data are representative of 2 independent experiments with mean ± SEM. n = 4–6 mice per group. Student’s t test, *P < 0.05, **P < 0.01, and ***P < 0.001.