Atorvastatin promotes the expansion of myeloid‐derived suppressor cells and attenuates murine colitis

Lei, Aihua; Yang, Qiong; Li, Xing; Chen, Haiwen; Shi, Maohua; Xiao, Qiang; Cao, Yingya; He, Yumei; Zhou, Jie

doi:10.1111/imm.12662

Cited by 38 publications

(37 citation statements)

References 59 publications

(102 reference statements)

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“…In this context, a noninvasive method of monitoring therapeutic response would be of great benefit to patients. We investigated whether MPIO-αMAdCAM-1 enhanced imaging can detect the effects on MAdCAM-1 expression of statin and antibodies against tumor necrosis factor (TNF) that have been shown to reduce leucocyte infiltration in acute and chronic DSS-induced colitis respectively( 20–22 ). First in the acute colitis model, we randomized the mice to receive either atorvastatin per os (20 mg/kg) or vehicle (water) for 72 hours after the five days of 2% DSS treatment ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Fournier

Lizarrondo

Rateau

et al. 2019

Preprint

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One Sentence Summary: Molecular magnetic resonance imaging allows non-invasive evaluation of mucosal inflammation in clinically relevant experimental models. ABSTRACTMucosal tissues line the digestive, respiratory, urinary, mammary and reproductive tracts and play critical roles in health and disease as the primary barrier between the external world and the inner body. Clinical evaluation of mucosal tissues is currently performed using endoscopy, such as ileocolonoscopy for the intestinal mucosa, that causes significant patient discomfort and can lead to organ damage. Here, we developed a new contrast agent for molecular magnetic resonance imaging (MRI) that is targeted to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), an adhesion molecule overexpressed by inflamed mucosal tissues. We investigated the diagnostic performance of molecular MRI of MAdCAM-1 to detect mucosal inflammation in several models of acute and chronic intestinal inflammation in mice. We demonstrated that molecular MRI of MAdCAM-1 reveals disease activity and can evaluate the response to inflammatory treatments along the whole intestinal mucosa in clinically relevant models of inflammatory bowel diseases. We also provide evidence that this new technique can detect low, subclinical levels of mucosal inflammation.Molecular MRI of MAdCAM-1 has thus potential applications in early diagnosis, longitudinal follow-up and therapeutic response monitoring in diseases affecting mucosal tissues, such as inflammatory bowel diseases.Recently, we and others reported the use of a new family of contrast agents for molecular MRI based on micro-sized particles of iron oxide (MPIO) that displays a dramatically higher sensitivity than classically used nano-sized particles(9-12). Thanks to an artefact known as the blooming effect, MPIO appear around 50 times larger than their actual size on iron sensitive T2*-weighted images (12). This characteristic of MPIO makes them particularly interesting for imaging mucosal tissues, since these tissues measure only a few hundred micrometers of thickness in physiological conditions and are thus hardly visible on unenhanced MRI. In the present study in mice, we developed a new MPIO-based contrast agent for MRI targeted to MAdCAM-1 (thereafter named MPIO-αMAdCAM-1). In three different models of intestinal inflammation, including lipopolysaccharides (LPS) induced endothelial activation, dextran sodium sulfate (DSS) induced colitis and trinitrobenzene sulfonic acid (TNBS) induced colitis(13), we demonstrated that this contrast agent allows detection of mucosal inflammation, quantification of disease activity and assessment of the mucosal response to anti-inflammatory treatments.

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Section: Resultsmentioning

confidence: 99%

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Fournier

Lizarrondo

Rateau

et al. 2019

Preprint

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“…Another option are statins, which are cholesterol lowering drugs, also described to induce immunosuppression. This was confirmed in acute and chronic dextran sodium sulfate (DSS)-induced colitis in mice, where statin-induced attenuation of colitis was due to expansion of MDSC ( 264 ).…”

Section: Recruiting Mdsc and Mdsc-exo In Autoimmune Diseasementioning

confidence: 87%

Janus-Faced Myeloid-Derived Suppressor Cell Exosomes for the Good and the Bad in Cancer and Autoimmune Disease

Zöller

2018

Front. Immunol.

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Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells originally described to hamper immune responses in chronic infections. Meanwhile, they are known to be a major obstacle in cancer immunotherapy. On the other hand, MDSC can interfere with allogeneic transplant rejection and may dampen autoreactive T cell activity. Whether MDSC-Exosomes (Exo) can cope with the dangerous and potentially therapeutic activities of MDSC is not yet fully explored. After introducing MDSC and Exo, it will be discussed, whether a blockade of MDSC-Exo could foster the efficacy of immunotherapy in cancer and mitigate tumor progression supporting activities of MDSC. It also will be outlined, whether application of native or tailored MDSC-Exo might prohibit autoimmune disease progression. These considerations are based on the steadily increasing knowledge on Exo composition, their capacity to distribute throughout the organism combined with selectivity of targeting, and the ease to tailor Exo and includes open questions that answers will facilitate optimizing protocols for a MDSC-Exo blockade in cancer as well as for strengthening their therapeutic efficacy in autoimmune disease.

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“…[49][50][51] It is also plausible that schweinfurthins modify the accumulation or activity of regulatory cells as has been demonstrated with other classes of cholesterol modulating drugs. 52,53 One such drug, liver-X nuclear receptor beta (LXRβ) agonist RGX-104, which lowers cholesterol levels by inhibiting transcription of key genes of cholesterol biosynthesis (eg, HMG-CoA reductase), reduced myeloid derived suppressor cells (MDSC) in both tumor-bearing mice and cancer patients. 54 This study also showed that RGX-104 in combination with αPD-1 elicits a greater anti-tumor effect than αPD-1 alone in vivo, but the agonist had no direct activity on T cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity

et al. 2018

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2019) Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity, OncoImmunology, 8:2, e1539614, ABSTRACT Metastatic melanoma is a significant clinical problem with a 5-year survival rate of only 15-20%. Recent approval of new immunotherapies and targeted inhibitors have provided much needed options for these patients, in some cases promoting dramatic disease regressions. In particular, antibody-based therapies that block the PD-1/PD-L1 checkpoint inhibitory pathway have achieved an increased overall response rate in metastatic melanoma, yet durable response rates are reported only around 15%. To improve the overall and durable response rates for advanced-stage melanoma, combined targeted and immune-based therapies are under investigation. Here, we investigated how the natural products called schweinfurthins, which have selective anti-proliferative activity against many cancer types, impact anti-(α)PD-1-mediated immunotherapy of murine melanomas. Two different compounds efficiently reduced the growth of human and murine melanoma cells in vitro and induced plasma membrane surface localization of the ER-resident protein calreticulin in B16.F10 melanoma cells, an indicator of immunogenic cell death. In addition, both compounds improved αPD-1-mediated immunotherapy of established tumors in immunocompetent C57BL/6 mice either by delaying tumor progression or resulting in complete tumor regression. Improved immunotherapy was accomplished following only a 5-day course of schweinfurthin, which was associated with initial tumor regression even in the absence of αPD-1. Schweinfurthin-induced tumor regression required an intact immune system as tumors were unaffected in NOD scid gamma (NSG) mice. These results indicate that schweinfurthins improve αPD-1 therapy, leading to enhanced and durable anti-tumor immunity and support the translation of this novel approach to further improve response rates for metastatic melanoma. ARTICLE HISTORY

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Atorvastatin promotes the expansion of myeloid‐derived suppressor cells and attenuates murine colitis

Cited by 38 publications

References 59 publications

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Janus-Faced Myeloid-Derived Suppressor Cell Exosomes for the Good and the Bad in Cancer and Autoimmune Disease

Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity

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