A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment

Li, Mingyue; Xing, Shugang; Zhang, Haiying; Shang, Siqi; Li, Xiangxiang; Ren, Bo; Li, Gaiyun; Chang, Xiaona; Li, Yilei; Li, Wei

doi:10.3892/or.2016.4547

Cited by 21 publications

(17 citation statements)

References 45 publications

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“…Thus, are involved in the development of an inflamed TME by regulating the activity of Tregs and immune suppressive myeloid cells (102). A combination of matrix metalloproteinase (MMP) inhibitors with an experimental mammary cancer model delayed tumor growth, reduced metastases formation and the percentage of Tregs and MDSCs as well as microvessel density (103). Thus, ECM components might serve as biomarkers to improve patients' stratification, but also could be used as therapeutic targets in combination with immunotherapies (104).…”

Section: Novel Strategiesmentioning

confidence: 99%

Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity

Seliger

2019

Front. Immunol.

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Treatment of cancer patients has been recently revolutionized by the application of various immunotherapeutics. However, the response rates are still limited ranging between approximately 20 and 40% suggesting that combinations of immunotherapy with conventional treatment, like chemotherapy, radiation, epigenetic modulators, targeted therapies using small molecules as well as other (immuno) therapeutics, might be an option to increase systemic anti-tumor immunity. It is postulated that different non-immune based therapies in combination with immunotherapies could reprogram the immune suppressive tumor microenvironment and enhance the immunogenicity of tumor cells leading to an improved therapeutic efficacy and a better patients' outcome. Despite there exist various examples of increased objective responses achieved by adding these different therapies to immunotherapies, strategies for rational and evidence-based design of checkpoint inhibitor combinations to maximize the clinical benefit for patients are urgently required. Therefore, the main purpose of this review is to summarize recent results obtained from experimental models and clinical trials to enhance tumor immunogenicity by combining immunotherapy with other therapeutic options to maximize patients' outcome and minimize adverse events.

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Section: Novel Strategiesmentioning

confidence: 99%

Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity

Seliger

2019

Front. Immunol.

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“…MMPs mediate a range of biological functions, such as degradation of various molecules for cell adhesion and modulation of cellular and extracellular matrix interactions [ 11 ]. Recent studies have shown that MMPs are highly associated with the microenvironment of tumors and immune cells and that targeting MMPs may overcome the barrier of immune suppression [ 11 , 12 ]. For example, MMPs process CCL/MCP and CXCL chemokines and their receptors to modulate inflammatory and immune responses [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

Kuang

Xie

et al. 2020

Genome Med

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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.

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“…Mature T lymphocytes can be divided into two subsets: CD4 + and CD8 + [32, 33]. CD4 + cells are T helper cells that aid in secreting numerous cytokines and enhance the killing effect of CD8 + cells in tumors [34]. CD8 + cells are cytotoxic and suppressor T cells and act as important effector cells [35].…”

Section: Resultsmentioning

confidence: 99%

Optimization of the fermentation process of Cordyceps sobolifera Se-CEPS and its anti-tumor activity in vivo

Yang

Zhang

2016

J Biol Eng

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BackgroundCordyceps sobolifera (C. sobolifera) isolated from cicadae was used as the starting fungus to produce selenium-enriched C. sobolifera extracellular polysaccharide (Se-CEPS). An orthogonal experimental design based on a single-factor experiment was used to optimize the C. sobolifera fermentation conditions, including the potato juice, peptone, and KH2PO4 concentrations. Ultraviolet (UV) and infrared (IR) analyses of CEPS and Se-CEPS were conducted, as well as an in vivo anti-tumor analysis.ResultsUnder optimal conditions (i.e., 40 potato juice, 0.4 KH2PO4, and 0.5 % peptone), the fermentation yield of Se-CEPS was 5.64 g/L. UV and IR spectra showed that Se-CEPS contained a characteristic absorption peak of a selenite Se = O double bond, demonstrating the successful preparation of Se-CEPS. Activity tests showed that Se-CEPS improved the immune organ index, serum cytokine content, and CD8+ and CD4+ T lymphocyte ratio in colon cancer CT26 tumor-bearing mice, thereby inhibiting tumor growth. When combined with 5-FU, Se-CEPS reduced the toxicity and enhanced the function of 5-FU.ConclusionThe result of these experiments indicated that orthogonal experimental design is a promising method for the optimization of Se-CEPS production, and the Se-CEPS from C. sobolifera can improve the anti-tumor capacity of mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s13036-016-0029-0) contains supplementary material, which is available to authorized users.

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A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment

Cited by 21 publications

References 45 publications

Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity

Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity

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

Optimization of the fermentation process of Cordyceps sobolifera Se-CEPS and its anti-tumor activity in vivo

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