Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1.

Abstract

BACKGROUND:

Immune checkpoint blockade (ICB) therapy has demonstrated considerable clinical benefit in several malignancies, but has shown favorable response in only a small proportion of cancer patients. Recent studies have shown that matrix metalloproteinases (MMPs) are highly associated with the microenvironment of tumors and immune cells. However, it is unknown whether MMPs are involved in immunotherapy.

METHODS:

Here, we used integrative analysis to explore the expression landscape of the MMP family and its association with immune features across multiple cancer types. We used T cell cytotoxicity-mediated tumor killing assay to determine the co-cultured T cell activity of SB-3CT, an MMP2/9 inhibitor. We then used in vitro assays to examine the regulating roles of SB-3CT on PD-L1. We further characterized the efficacy of SB-3CT, in combination with anti-PD-1 and/or anti-CTLA4 treatment in mouse models with melanoma and lung cancer.

RESULTS:

Our computational analysis demonstrated a strong association between MMP2/9 and immune features. We demonstrated that inhibition of MMP2/9 by SB-3CT significantly reduced the tumor burden and improved survival time by promoting anti-tumor immunity. Mechanistically, we showed that SB-3CT treatment significantly diminished both mRNA and protein levels of PD-L1 in cancer cells. Pre-clinically, SB-3CT treatment enhanced the therapeutic efficacy of PD-1 or CTLA-4 blockade in the treatment of both primary and metastatic tumors.

CONCLUSIONS:

Our study unraveled novel molecular mechanisms regarding the regulation of tumor PD-L1 and provided a novel combination therapeutic strategy of SB-3CT and ICB therapy to enhance the efficacy of immunotherapy.

• Authors: Youqiong Ye, Xinwei Kuang, Zuozhong Xie, Long Liang, Zhao Zhang, Yongchang Zhang, Fangyu Ma, Qian Gao, Ruimin Chang, Heng-Huan Lee, Shuang Zhao, Juan Su, Hui Li, Jingbo Peng, Huifang Chen, Minzhu Yin, Cong Peng, Nong Yang, Jing Wang, Jing Liu, Hong Liu, Leng Han, Xiang Chen
• Journal: Genome medicine (Genome Med) Vol. 12 Issue 1 Pg. 83 (09 28 2020) ISSN: 1756-994X [Electronic] England
• PMID: 32988398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• Heterocyclic Compounds, 1-Ring
• Immune Checkpoint Inhibitors
• Matrix Metalloproteinase Inhibitors
• SB 3CT compound
• Sulfones
• MMP2 protein, human
• Matrix Metalloproteinase 2
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Animals
• B7-H1 Antigen (genetics, metabolism)
• Biomarkers, Tumor
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterocyclic Compounds, 1-Ring (pharmacology)
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Immunologic Surveillance (drug effects)
• Lymphocytes (immunology, metabolism)
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Matrix Metalloproteinase Inhibitors (pharmacology)
• Melanoma, Experimental
• Mice
• Sulfones (pharmacology)
• Tumor Microenvironment