MMP2 and TLRs modulate immune responses in the tumor microenvironment
Luciana R. Muniz-Bongers, … , Miriam Merad, Nina Bhardwaj
Luciana R. Muniz-Bongers, … , Miriam Merad, Nina Bhardwaj
Published May 25, 2021
Citation Information: JCI Insight. 2021;6(12):e144913. https://doi.org/10.1172/jci.insight.144913.
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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 3

Smaller tumor growth and differential tumor microenvironment in Tlr2–/– Tlr4–/– mice.

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Smaller tumor growth and differential tumor microenvironment in Tlr2–/– ...
In total, 3 × 105 B16 F1 cells were injected s.c. into WT or Tlr-deficient mice, and tumors were analyzed 15–19 days later. (A) Tumor volume in WT, Tlr2–/–, Tlr4–/–, and Tlr2–/– Tlr4–/– mice at day 15. Data are representative of 4 independent experiments with mean ± SEM. *P < 0.05. Two-way ANOVA with Dunnett’s post hoc test. (B) Tumor growth kinetics between WT and Tlr2–/– Tlr4–/– mice during the course of 19 days. (C) Tumor weight (mg) at day 18–19. (A–C) Data are representative of 5 independent experiments with mean ± SEM. **P < 0.01 and ***P < 0.001. Two-way ANOVA with Sidak’s correction for multiple comparisons. (D–I) CyTOF analysis of lymphoid and myeloid panels in the TME at day 19 between WT and Tlr2–/– Tlr4–/– mice. viSNE plot of immune, stromal, and tumor cell clusters present in the lymphoid (D) and myeloid (E). Comparison between WT and Tlr2–/– Tlr4–/– mice in the lymphoid (F) and myeloid (G), highlighting differentially expressed clusters (dotted lines). Statistically significant clusters from the lymphoid (H) and myeloid (I) are identified. Data are representative of 2–4 mice with mean ± SEM. *P < 0.05 and **P < 0.01. P values were adjusted using FDR. Statistical analysis was performed using binomial generalized linear mixed-effects model (GLMM). (J) IF staining of MMP2 (green), CD45 (red) and DAPI (blue). Scale bars: 200 μm for the top panel, 50 μm for the bottom panel.