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

Publication date: Sep 28, 2020

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.

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.

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.

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.

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Concepts Keywords
Assay Microenvironment tumors
Blockade Anti tumor
CTLA4 Immunotherapy
Cytotoxicity Immune system
Immune Cells Clinical medicine
Immune Surveillance Medical specialties
Immunotherapy Cancer immunotherapy
Inhibitor Clusters of differentiation
Lung Cancer Checkpoint inhibitor
Malignancies Matrix metallopeptidase
Matrix Metalloproteinases MMP2
Melanoma Tumor microenvironment
Metastatic
Microenvironment
MMP
MMP2
MMP9
MRNA
Small Molecule
Tumor

Semantics

Type Source Name
disease MESH tumor
disease MESH melanoma
pathway KEGG Melanoma
disease MESH lung cancer
pathway REACTOME Reproduction
disease MESH bladder cancer
pathway KEGG Bladder cancer
disease MESH death
drug DRUGBANK Ipilimumab
drug DRUGBANK Cefaclor
disease MESH tumor immune escape
drug DRUGBANK Batimastat
drug DRUGBANK Tanomastat
drug DRUGBANK Marimastat
disease MESH breast cancer
pathway KEGG Breast cancer
disease MESH carcinogenesis
drug DRUGBANK Esomeprazole
drug DRUGBANK Honey
drug DRUGBANK Streptomycin
disease MESH infection
drug DRUGBANK Phosphate ion
drug DRUGBANK Gentian violet cation
drug DRUGBANK Aspartame
drug DRUGBANK Edetic Acid
drug DRUGBANK Coenzyme M
disease MESH suffering
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Trestolone
disease MESH squamous carcinoma
disease MESH renal
disease MESH uveal melanoma
pathway KEGG Apoptosis
disease MESH tic
disease MESH carcinoma
drug DRUGBANK Hyaluronic acid
disease MESH growth
disease MESH **p
drug DRUGBANK Proline

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